CN102224410B - Imaging analyzer for testing analytes - Google Patents

Abstract

The invention provides analyzers that improve tests for detecting specific cellular, viral, and molecular targets in clinical, industrial, or environmental samples. The invention permits efficient and specific selection and sensitive imaging detection of individual microscopic targets at low magnification. Automated embodiments allow efficient walk-away, on-demand, random-access high-throughput testing. The analyzers perform tests without requiring wash steps thus streamlining engineering and lowering costs. Thus, the invention provides analyzers that can deliver rapid, accurate, and quantitative, easy-to-use, and cost-effective tests for analytes.

Description

Imaging analysis instrument for test analyte

Cross-Reference to Related Applications

This application claims the interests of the U.S. Provisional Application No. 61/099,830 of September in 2008 submission on the 24th, it passes through to draw With being expressly incorporated herein.

Background technology

Detect the importance of specific target.Method for detecting specific molecule, cell and viral target, is medical science Master tool with Disease Diagnosis of Veterinary, environmental test and Industrial quality control.Clinical medicine is used for detect the side of specific target The example of method includes sales counter quick pregnancy tests on sale, the microorganism for measuring the resistance to certain antibiotics for the infectious agent Learn supermatic test of cancer markers in culture experiment, and blood sample.Detect the pathogen contamination thing in food, be used for Active component in the high frequency zone of the candidate compound of drug development, pharmaceutical, illustrate depend on specific for measuring The industrial production purposes of the method for the presence of target.The environmental application testing specific target is needed to include, detection water supply pollution, sky Biothreat agents and the fungal contamination of family that gas is propagated.

Mark target.One is used for detecting that specific cells, viral or molecule important aspect are, with optically detecting Mark marking target.Can specifically or non-specifically mark target.By special with the target containing optical markings The binding molecule of the opposite sex is marked, and can specifically mark target.Target specific marker can have different types of Bound fraction, including macromolecular (For example,Antibody, protein receptor, nucleic acid, carbohydrate and agglutinin) and small molecule (Example As,Hormone, drug abuse, metabolin).The detectable signal emission part of target specific marker can be sent out using multi-signal Penetrate feature, light including fluorescence, phosphorescence, chromogen（chromogenicity）, chemiluminescence, light scattering and Raman scattering.

Or, non-specifically can mark target that is, can mark together with the other entities in sample Remember them.For example, it is possible to be with all cells in DNA dye marker sample, or can be with reference to all such molecules Mark and to mark all lipoprotein.Then specifically can detect non-specific using following specific selections of target The target of ground mark.

Specifically select target.Target is specific to be selected to be typically important for the target of detection mark. Specific selection is frequently used for physically isolating target from the entity of other marks, also from unconjugated mark.For example, Can be used for the target being complexed mark with the coated magnetic-particle of the specific antibody of target.Magnetic force is applied to this complex compound, Then the target of mark can be deposited from the teeth outwards, and the entity marking and unconjugated mark then do not deposit.Or, by catching Obtain that is to say, that passing through to be attached to by the specific bound fraction of target（Such as antibody）On coated surface, spy can be carried out The opposite sex selects.Specific selection can occur before or after target marks.

After specific selection and target mark, generally remove unconjugated in continuous washing step from reactant Mark, and select to retain the target specifically selecting, for subsequent detection.Washing step needs the undesirable work of user （In the case of manual experimental technique）Thereby increases and it is possible to need complicated liquid handling engineering（In automated system）.Some skills Art, such as lateral flow method, specifically capture the mark on film or the surface of solids using passive capillarity from The target of note washes down unconjugated mark and the mark non-specifically combining.Lateral flow method is that manual experiment simplifies washing Function, but these methods are possibly insensitive, and it is not suitable for the format high throughput test on automation platform.

Carry out the target of count tag using imaging.Imaging is specifically selecting on detection surface for detection The powerful approach of the target of mark.The optical signal that each point from detection zone is launched is mapped in image imaging method Corresponding points.On the contrary, non-imaged detection method generally integrates the optical signal launched from whole detection zone.

Some imaging methods can detect and count the target of single marking.Compared with detection zone integration method, calculate special The target marking can lead to the detection of very low target level different in naturely.The sensitivity of the target method of counting based on image is excellent Point is derived mainly from following facts, reduces with target level, and optical signal is held substantially constant with the ratio of background.On the contrary, right In detection zone integration method, reduce with target level, signal is reduced with the ratio of background.

One class method is by setting up image with micro- beam system scan test section.Scan method ratio uses Digital Arrays Row detector (For example,CCD or CMOS camera) to calculate the side of the target specifically marking in whole detection zone simultaneously Method expends the more time.

The large area imaging in low magnifying power counting for sensitive target.Certain methods use high magnifying power micro- Art is calculating single miniature target.Micro-imaging lacks sensitivity, because each image only samples small area.Can be to bigger Area continuous imaging, but the acquisition of many images is laborious, costliness and time-consuming.Or, it is possible to use in low amplification The large area imaging of rate, individually detects and calculates the miniature target of mark.Low magnifying power imaging can allow in single image The middle miniature target of a small amount of calculating in large area relatively.

Do not need to wash the method removing free label from the target specifically marking.Have been developed for several not The method needing washing, the target that the specific bound fraction of target that its detection marks specifically is complexed.One class method Using unless they combine the mark of not transmission signal during target.These marks have restriction, because they will not be launched enough Strong signal is used for effective large area detection of the target of single marking.Another kind of method washed is not needed to pass through liquid phase barrier Selected, to isolate the target complex compound of mark from unconjugated mark.The program use detection zone integrate rather than Sensitive graphical analysis, thus lack high sensitivity.

Detect the analyzer that the test of specific target is used using imaging.For the miniature target to single marking The analytical instrument of imaging is usually used high magnifying power that target is imaged.For example, there is Microscope optics and Digital photographic The analyzer of machine can detect the cell of the single marking in the light-transparent substrate in the hole being deposited on microwell plate.Except inherently scarce It is derived from less beyond sensitivity and the imaging efficiency of zonule micro-imaging, these analyzers typically require multiple washing steps and make a return journey The entity marking except unconjugated mark and non-specifically.

Have been developed for the analyzer based on imaging that several use large area automate digital imagery, for detecting simultaneously The target of single marking.In order to detect single target, these analyzers have to carry out the washing step of repetition or pass through capillary Stream is washed.It is limited to be effectively tested bulk sample using the analyzer of the test of device needing capillary stream (For example,1 ml) or be configured for automating format high throughput test.

Content of the invention

The invention provides improved analyzer, it is entered using the optics that can detect the single target optically marking Row large area imaging, and eliminate the needs to washing step.By being imaged to the target of single marking without washing step, The invention provides sensitive and quantitative test, reduce cost and the complexity of automation mechanized operation simultaneously.

In one aspect, the present invention characterizes imaging analysis instrument, and it includes housing, and described housing accepts the sample equipped with sample Product container, and there is detection zone, described detection zone has >=the line of shortest length size of 1mm, there may be in detection sample Target；For selection power being put on the assembly of shuttle；The photoelectricity battle array configuring for the large area imaging of detection zone Row detector；It is less than 5 times with amplifying（For example, less than 2 times）Image forming optics.In different embodiments, described choosing Power of selecting is less than 0.5 mm and average with the average speed rolling average diameter more than 0.5 mm/min in the liquid of shuttle Density is less than 2 g/cm³The magnetic-particle of n is more than the distance of 5 mm, and described shuttle is maintained at the fixed position of analyzer, The density of wherein said liquid and viscosity are substantially identical with salt solution.Device for applying selection power can include having being more than The shortest linear size of 10 mm and the magnet of the intensity of magnetization more than 3.5 kJ (kilojoule)s/cubic meter.Analyzer can also include One or more automatic gathering on detection zone；For guaranteeing the mechanism of the fixed range between detector and detection zone； The irradiation bomb (for example, light emitting diode) of shuttle；The liquid transfer device of automation；Cause liquid in shuttle The mechanism of flowing；Can between the position on analyzer mobile example container robot stand；Can be on analyzer The carousel mechanism of mobile example container between position；Can between the position on analyzer mobile example container machine Tool follower；Bar code readings bar code device；For receiving the incubator of shuttle, it has and is stably maintained at temperature set-point 2 degrees Celsius in mean temperature shell；Printer, electronic monitor and/or the system for connecting external communication network； Automatically shuttle cleaner；One or more recipients that imaging is followed by by shuttle on analyzer；One or More waste liquid recipients；The integrated image analysis software with object lookup algorithm；With integrated planning software, for managing Manage movement between the diverse location of analyzer for one or more shuttles.Preferably, analyzer is received as single Or the importing of the shuttle as multiple units.Analyzer can also receive the shuttle having more than 8 mm height.

Imaging analysis instrument and its assembly is also illustrated in embodiment and accompanying drawing.

" washing " refers to such process, and it removes liquid from container or surface physics, and described liquid contains from target Undesirable component of thing, described target is different from undesirable component, be retained, select or capture in a reservoir or surface On.

The test of " not needing to wash " refers to such test, does not wherein detect target using washing step.

" analyzer " or " imaging analysis instrument " refers to such instrument, and it has permission detection zone defined herein and becomes simultaneously The array photo-detector of picture and image forming optics.Analyzer can have many other functions for strengthening detection, including For selection power is put on selected section, transport or the module incubating.

" hole " refers to accommodate the container of liquid.Hole generally has >=hole depth of 1 mm.

" imaging hole " refers to can be used for detect the hole of the target of mark by imaging.Imaging hole has detection surface, On said surface, imaging analysis instrument can detect the target particle of mark.It is located at the light inspection of detection surface and imaging analysis instrument Survey the optical property that the material between device has the image checking of the target for supporting mark.For example, described material is typically Transparent, and there is in the spectral regions corresponding with the marker of the signal emission part of device low optical background.

" imaging hole depth " refers to the imaging hole distance along the axle perpendicular to detection surface.

" mat ", " density mat ", " liquid mat ", " mattress layer " or " fluid density mat " refers to that its density is more than and covers The substantially liquid level of cap rock.In the present invention, mat is present in imaging hole, positioned at detection surface and inclusion sample and experiment Between the liquid level of reagent.This mat provides the physical separation between experiment reagent and detection surface.Using selection, with selection The target of mark being partly combined moves through mat, and is deposited on and is imaged on detection surface.The dense liquids layer of mat The not selected signal emission part being partly combined is excluded from detection band.

" dyestuff " refers to add the material in reaction or mixture, and it disturbs the light investing or being derived from signal emission part Generate or transmission.Described dyestuff is reduced or eliminated the signal sending beyond detection zone, allows detection in detection zone simultaneously The signal that signal emission part derives.For the device including fluorescence signal emitting portion, dyestuff can absorb fluorescence excitation Frequency, fluorescent emission frequency or the light of the two.Different dye properties can be used for this purpose, including light scattering and absorption.? In different embodiments, described dyestuff can make signal be reduced at least 50%, 75%, 85%, 90%, 95% or even 99%.

" mat of dyeing " refers to the mat of dyestuff.The provider's reaction simultaneously of the mat of dyeing is from the thing of detection band Reason exclusion (changing with the density of tinctorial mat), prevents simultaneously or reduces signal from covering reaction to the transmission of detector (include with compacted zone dyestuff and change).

" sampler " refers to the device for collecting sample.The example of sampler includes swab, capillary, wiping Device, beaker, porous filter, water absorbing filter and suction nozzle.

" target " refers to cell, virus, molecule or the molecular complex being likely to be present in sample, is tested by the present invention It exists.

" target species " refers to one or more features that multiple targets have so that multiple target is considered for making It is identical for the experiment purpose being built with the present invention.For example, for the experiment for detecting all inhibition of HIV, described kind Class is HIV.Such experiment can detect all inhibition of HIV, and does not differentiate between HIV-1 and HIV-2 variant.In this case, target Species include HIV-1 and HIV-2.The purpose of another experiment is probably to distinguish HIV-1 with HIV-2.In this case, Every class HIV is considered different species.If experiment purpose is detection saccharomyces albicanses, 3 probes are considered for reality It is identical for testing purpose, because they have common trait, that is, they specifically combine saccharomyces albicanses, and quilt It is regarded as belonging to identical target species.

" species-binding molecule " refers to specifically combine the molecule of binding site or the molecular complex of species specificity Thing.The example of species-binding molecule is the nucleic acid probe of hybridizing genomic dna；Select in vitro or " evolution " has become special Property ground associated proteins on site aptamer；Antibody in conjunction with cellular antigens or haemocyanin；Specifically combine and swash Plain acceptor or binding molecule（Such as avidin）Part（Such as EGF or biotin）.If they are tied Close the binding site of different and non-overlapping species specificity, then 2 species-binding molecules are different.Can be according to it Molecular composition refer to species-binding molecule,For example,The oligonucleotides of species combination, probe, antibody, part etc..

" capture molecule " refers to the species-binding molecule being stably bound in surface, film or non-particulate other matrix.

Species-the binding molecule of " specifically combining " target species refers to such species-binding molecule, and it is in definition Conjugation condition under be combined as testing the essentially all target of the member of species of scanning, but substantially do not combine possibility It is present in the other molecules in sample.The number of species-binding molecule that target in the species of scanning is combined with respect to The number that target in such species is not combined, typically 2 times, 5 times, 10 times or big more than 50 times.

" signal element " refers to directly produce molecule or the particle of detectable signal.Phrase " directly producing " represents following things Real, that is, signal element is direct sources or the key regulator of detectable signal.Thus, if signal is derived from the light of fluorogen Son, then described fluorogen is the direct sources of photon, and is therefore signal element.If signal is the light being scattered by RLS particle Son, then described RLS particle is signal element.Or, if signal is the color development precipitated product transmission from horseradish peroxidase Or the light of scattering, then described chromogenic product is signal element.

One feature of signal element is, such element can not part so that each part produces and entirety phase Signal when (according to feature, not necessarily according to intensity).Thus, 2 nM diameter quantum dots are signal elements, because splitting its meeting Change the feature (emission spectra) of the nanocrystal obtaining.The 5 m particles with the fluorescent dyes such as fluorescein dipping are not letters Number radiated element, because it is segmented into part so that each part has the signal emission characteristic suitable with whole grain.Phase Instead, molecular fluorescence element is signal radiated element.Signal generation enzyme (For example,Luciferase, alkaline phosphatase, horseradish peroxidase Enzyme) detectable product be also considered signal element.(, when there is precursor to signal in or their precursor for such signal element During the chemical conversion of element) can be diffusible substance, insoluble product and/or unstable intermediate.For example, enzyme alkaline phosphatase By chemical luminous substrate CDP-Star (NEN;Catalog number (Cat.No.) NEL-601) change into activation products, it is the signal element of transmitting photon Part.

" signal emission part " refers to such molecule, particle or material, and it includes or produces (in the context of enzymes) one Individual or more signal elements, and conjugated or can be conjugated on species-binding molecule.Signal emission part can covalently or Noncovalently, either directly or indirectly (For example,By one or more attachments or " chemical linkers " part, or pass through Two parts being conjugated on identical particle) it is attached on species-binding molecule.The example of signal emission part includes carboxylated Quantum dot；It is modified into the fluorogen with reference to nucleic acid probe or antibody probe（Such as texas Red）；Streptavidin- Coated fluorescence granules of polystyrene (it can be conjugated on the associated proteins of biotinylated species specificity)；Containing repetition The rolling-circle replication product of nucleotide sequence, each described sequence can hybridize several oligonucleotides, and described oligonucleotides is repaiied with fluorescence The nucleotides of decorations is tail, and contains the oligonucleotide binding of species specificity in 5' end.Signal emission part can include Physically different elements.For example, in some cases, described signal emission part is to be conjugated to species-binding molecule (for example Antibody) on enzyme (For example,Alkaline phosphatase).When alkaline phosphatase substrate (For example,CDP-Star or BM is purple, comes respectively From NEN and Roche) be converted to signal element product (For example,The unstable intermediate of transmitting photon, or precipitable color development Product) when, produce signal.For species-binding molecule, enzymatic signal emission part and different time be applied to reaction in Substrate, it is not rare.

" particle " refers to be smaller in size than 50 microns of matrix.A group or a collection of particle be size be defined as particulate samples The average measurement of the longest orthogonal dimension pair.To being such particle orthogonal dimension pair, its length summation is this to the longest orthogonal dimension The maximum of all this summation of particle.If the sample of 2 particles is respectively provided with 1 micron × 2 microns and 2 microns × 3 The longest orthogonal dimension pair of micron, the average measurement of the longest orthogonal dimension pair is 2 microns [(1+2+2+3)/4=2 micron].? The average measurement of the longest orthogonal dimension pair of grain sample is, for example, less than 50 microns, less than 20 microns or less than 5 microns.

Many particles have some solid features.However it is possible to not be rigid molecular scaffold or complex compound is also defined For particle.For example, dendritic or other branched molecular structure are considered particle.Similarly, liposome is another kind of Grain.Particle can in conjunction with or be conjugated on signal element.Term through conventional their yardstick of reflection or geometry, expression Grain.For example, term nanosphere, nano particle or nano-beads are used for representing the particle along the measurement of any given axle less than 1 micron. Similarly, term microballoon, particulate or microballon are used for representing the particle along the measurement of any given axle less than 1 millimeter.The reality of particle Example includes latex particle, polyacrylamide particle, magnet particles, ferrofluid (magnetic nanoparticle), quantum dot etc..

" marking particle " refers to can be specifically with reference to target and produce the particle of signal.Marking particle is conjugated to signal In emitting portion and species-binding molecule.

" target:Marking particle complex compound " refers to the marking particle that one or more of targets specifically combine.

" signal characteristic " (the signal character) of signal element or signal section refer to by described signal element or One or more aspects of the signal that signal emission part produces, it can be used for and other signal elements or signal emission part Subregion is separately.For example, the signal characteristic with fluorescein and the signal emission part of rhodamine mark isFluorescence.Radiation transponder Feature beRadio frequency.The example of photon signal emission characteristic is fluorescence, light scattering, phosphorescence, reflectivity, absorbance, chemiluminescence And bioluminescence.All（In addition to last 2 examples）Photon signal emission characteristic depends on external irradiation (such as white light Source, lasing light emitter or daylight).On the contrary, CL and BL is independently of the signal emission characteristic of external light source.

" marker " (signal signature) refers to the combination of the signal emission part of Binding experiment target species Characteristic signal emission characteristics.In conjunction with 4 antibody-likes（One of them is conjugated on fluorescein molecule, and wherein 3 class rhodamines divide Subfix closes）Target have the combination with fluorescein and rhodamine the absorbance of weighting and transmitting profiling marker.

" selection power " refers to for capturing, separating, power that is mobile or completely cutting off target.The example of selection power includes gravity, magnetic Power, potential, centrifugal force, centripetal force, buoyant density and pressure.By acting solely on the selection power in target, can be with running target Thing.Or, selection power can be made to specifically act on and (to see below definition) in the target being combined with selected section.

Apply selection power to include come the example to move target：The centrifugation of target；It is attached to the magnetic of the target on magnetic-particle Sexual behavior mode；Gravitational settling with the target of metallic particles mark；With by vacuum filter, target is deposited on perforated membrane.Under Other examples of the application of selection power are included in the embodiment in face.

" selected section " refers to such atom, molecule, particle or other entity, and it can be conjugated to species-combination point On son, and give species-binding molecule imparting by selection power by optionally capture, the ability separating, moving or completely cut off.Work as kind Class-binding molecule:When selected section complex compound specifically combines target, described target generally can also be selected by selection power Capture to selecting property, separate, moving or completely cutting off." selective " represent selection power to the movement of selected section and the entity of combination The preferential neurological susceptibility that gives exceedes the unconjugated entity of selected section.

Paramagnetic particle and ferritin are the examples of selected section.The silica dioxide granule of the densification sunk in the solution is another One class selected section.When being coated by species-binding molecule and combine microorganism target, such particle can cause target in water Sink in solution, thus lead to target and other unconjugated Component seperation of sample combining.

" general plane " surface or substrate refer to such surface, and its imaginary plane that can abreast align is so that work as When point from any 1 mm × 1 mm square this surface is to the closest approach measurement distance on imaginary plane, average departure From absolute value be less than 50 microns.

" detection surface " refers to, in certain embodiments of the invention, deposits the general plane base of target in the above The surface at bottom.In the embodiment using photon signal emission characteristic, if described detection surface is printing opacity, by detection Any surface on surface, it is possible to achieve detection.If described detection surface is lighttight, by the detection surface of deposition target Simultaneously, it is possible to achieve detection.

" detection zone " refers to the detection surface region simultaneously analyzed by the present invention or detection band.The longest linear of detection zone Size is typically larger than 1 mm, for example, more than 5 mm, 10 mm or 15 mm.For example, by including collection lens and CCD chip The slide that Optical devices are imaged simultaneously partly can measure 0.8 cm × 0.5 cm.Then detection zone is 0.4 cm².

" detection band " refers to can detect the volume of target wherein.Detection band has and detection zone identical yardstick, but It is the corresponding depth of depth having with can detecting and differentiate marking particle wherein.The depth of detection band therefore depends on Threshold value standard for the positive signal that scores.When using optical detection, the depth of detection band depends on the optical depth of field.

" the longest yardstick " of detection zone refers to the maximum length line that can draw between 2 points on detection zone periphery. For example, if detection zone is the rectangle being measured as 0.3 cm × 0.4 cm, the longest yardstick of detection zone is diagonal 0.5 cm. If detection zone is semi-major axis length be 7 mm and semi-minor axis length be 2.5 mm ellipse, the longest yardstick of detection zone is 14 mm.

" short-scale " of detection zone refers to the minimum length line that can draw between 2 points on detection zone periphery. For example, if detection zone is the rectangle being measured as 0.3 cm × 0.4 cm, the short-scale of detection zone is diagonal 0.3 cm. If detection zone is semi-major axis length be 7 mm and semi-minor axis length be 2.5 mm ellipse, the short-scale of detection zone is 5 mm.

" large area detection " or " large area imaging " refer to the method for detecting miniature target, and wherein detection zone (passes through The region that detection means is analyzed simultaneously) it is far longer than target.Detection zone for large area detection has the >=linear chi of 1 mm Degree.On the contrary, miniature target is substantially less, is generally less than 50 m at least 2 orthogonal dimension measurements.The reality of large area detection Example includes：With CCD camera, 9 mm diameter detection zones are imaged；Swept by the CCD rectilinear scanner with having the long size of 1 cm Retouch, to 2 cm × 1 cm rectangle imagings；Using being directly exposed to photographic film, to 4 cm × 4 containing microorganism target Cm optical filter is imaged；With the miniature target in quick lateral flow strip test, in visual inspection and 1 cm × 3 cm test block Corresponding color spot.

" being conjugated " or " stable bond " refers to the physical bond between 2 entities, the mean half-life of wherein combination be In PBS 4 DEG C at least 1 day.

Detection zone partly in " simultaneously detect " target refer to detect in one step the detection table from general plane The signal of face part.Using CCD chip, visual inspection or the signal integration based on photodiode, big face is carried out to the target of detection zone Long-pending imaging, is the example simultaneously detecting.

" sample " refers to scan the material of the presence of target by the present invention.

" direct visual inspection " refers to the visual inspection under the not auxiliary of the Other Instruments in addition to Wearable correcting lens. For example, direct visual inspection can be used for detecting the pink reflected signal of nanogold particle in some quick lateral flow assay.

" photoelectric detector " refers to photon signal is converted into artificial apparatus or the instrument of electric signal.The reality of photoelectric detector Example includes CCD-detector, photomultiplier detector and photodiode detector, for example, avalanche photodide.

" photoelectric array detector " refers to comprise the photoelectric detector of the sensitive array of pixel of independent light.Photoelectricity battle array The example of row detector includes CCD-detector and CMOS detector.

" irradiation " refers to be irradiated with electromagnetic radiation.The electromagnetic radiation of different wave length can be used for irradiation.It includes, for example, Wave length radiation in X-ray, ultraviolet, visible ray or infrared spectrum region.It should be pointed out that irradiation is not necessarily can Vision area.Irradiation preferably occur in the range of 190 to 1100 nm.

There is the signal element of " photon signal emission characteristic " or signal emission part refers to such signal element or letter Number emitting portion, it by the transmitting of photon, reflection, scattering, refraction, absorption, capture or can redirect or photon behavior Any other adjust or combination is detecting.There are the signal element of photon signal emission characteristic or some realities of signal emission part Example includes：Fluorogen texas Red (fluorescence signal emission characteristic);CDP-Star (chemiluminescence signal emission characteristic); Luciferase (bioluminescence signal emission characteristic);Resonant light scattering particle (light scattering signal emission characteristic);BM purple (light Absorb or color development signal emission characteristic);(absorb 2 long wavelength photons, and launch 1 shorter wavelength light with raising frequency phosphor Son).

PBS is phosphate buffered salt solution, and it contains:120 mM NaCl, 2.7 mM KCl and 10 mM phosphate delay Rush liquid (sodium salt) pH 7.4.

CCD is charge-coupled image sensor.

HTSH is H-TSH.

PSA is pressure sensitive adhesive.

RF ID is radio frequency identification.

Unless otherwise noted, the microbial strains describing in this manual are from U.S.'s allusion quotation of Virginia Manassas Type culture collection (ATCC) obtains.

Brief description

Fig. 1. imaging and light optic system sketch.(embodiment 1)

Fig. 2. graphical analysis:From the upper left corner counterclockwise input, ROI, the input amplified, the signal detecting, The fragment of detection.(embodiment 3)

Fig. 3. bar shaped magnetic combines the unit.(embodiment 2)

Fig. 4. the imaging between parallel bar magnet.(embodiment 2)

Fig. 5. cylindrical magnetic volume array.(embodiment 2)

Fig. 6. (real from the result of the test of the device with integrated growth and reagent modules and the contrast of desktop test Apply example 9).

Fig. 7. the system schematic of the analyzer simply not automated.(embodiment 4)

Fig. 8. the photo of the analyzer simply not automated.(embodiment 4)

Fig. 9. the analyzer software sketch of automation.(embodiment 6)

Figure 10. the monocyte sample instrument cylinder insertion of automation.(embodiment 7)

Figure 11. the monocyte sample instrument sample of automation adds.(embodiment 7)

Figure 12. the monocyte sample instrument system sketch of automation.(embodiment 7)

Figure 13. the monocyte sample instrument result output of automation.(embodiment 7)

Figure 14. format high throughput Automatic analyzer.(embodiment 8)

Figure 15. analyzer CAD sub-component as needed.(embodiment 9)

Figure 16. analyzer photo as needed.(embodiment 9)

Figure 17. cylinder embodiment.(embodiment 9)

Figure 18. analyzer electrical system as needed.(embodiment 9)

Figure 19. from the output formats of Automated Image Analysis software.(embodiment 8)

Figure 20. using the external view of the Automatic analyzer as needed of fixing V belt translation.(embodiment 10)

Figure 21. the interior views of Automatic analyzer as needed.(embodiment 10)

Figure 22. the front view of the concept map of cylinder analyzer as needed of automation.(embodiment 11)

Figure 23. the rearview of the concept map of cylinder analyzer as needed of automation.(embodiment 11)

Figure 24. transmission mechanism is transported in monoplane.(embodiment 12)

Figure 25. shockwave system software sketch.(embodiment 13)

Figure 26. cylinder used in the automation cylinder analyzer for format high throughput surge test.(embodiment 15)

Figure 27. the carrier of the cylinder in Figure 26.(embodiment 15)

Figure 28. for the cylinder analyzer of the automation of format high throughput surge test.(embodiment 15)

Figure 29. the interior views of format high throughput surge test analyzer.(embodiment 15)

Figure 30. the aloft process step on reason stroke ripple analysis of experiments instrument.(embodiment 15)

Figure 31. fluid container.(embodiment 14)

Figure 32. there is the sample holder of sample consumption product.(embodiment 14)

Figure 33. the functional entity of Platform and module conveyer belt.(embodiment 14)

Figure 34. business impact ripple detection platform architecture.(embodiment 16)

Figure 35. the once diagram of 3 Patient Sample A of pipette.(embodiment 16)

Figure 36. load sample holder.(embodiment 16)

Figure 37. sample is delivered to by instrument by sample tracking system.(embodiment 17)

Figure 38. compared with comparable machine, simple architecture and little contact area.(embodiment 17)

Figure 39. the functional entity of centralized laboratories analyzer.(embodiment 17)

Figure 40. the key element of centralized laboratories analyzer.(embodiment 17)

Figure 41. application state sketch.(embodiment 6)

Figure 42. pick up and put humanoid robot layout.

Figure 43. example workflow.

Figure 44. the sub-component that queuing is assembled with sample holder.(embodiment 14)

Figure 45. the view of liquid handling and agent treatment subsystem.(embodiment 14)

Figure 46. transfer pipet(te) combines the unit.(embodiment 14)

Figure 47. cup cleaning combination unit.(embodiment 14)

Figure 48. shock-wave detection Prototyping Platform.(embodiment 14)

Figure 49. the close-up illustration of liquid handling subsystem.(embodiment 14)

Figure 50. system control interface table (interface tab) 1.(embodiment 8)

Figure 51. system control interface table 2.(embodiment 8)

Figure 52. system control interface table 3.(embodiment 8)

Figure 53. system control interface table 4.(embodiment 8)

Figure 54. for the flat position selection window of Auto 2.(embodiment 8)

Figure 55. the main reagent container embodiment of display turbulence induced baffle plate and button.(embodiment 14)

Figure 56. mixing cup and SAW transducer sub-component.(embodiment 14)

Figure 57. magnet and optical sub-assembly.(embodiment 14)

Figure 58. carousel top view.(embodiment 14)

Figure 59. the method taking out liquid from cup.(embodiment 14)

Figure 60. capillary sample collection running stores.(embodiment 14)

Figure 61. sample obtains and distributes the combination of running stores.(embodiment 14)

Figure 62. four axle executors.

Figure 63. the embodiment that homogeneous magnetic selects.(embodiment 14)

Figure 64. fluid treatment sketch.(embodiment 14)

Figure 65. the photo of surge test cylinder.(embodiment 15)

Figure 66. there is the image that different magnetic select.(embodiment 2)

Figure 67. the example of deformable bag, described bag has the frangible seal it being worked by roller mechanism.

Figure 68. shockwave system sample collection.(embodiment 16)

Figure 69. movably quasi shock waves analysis instrument.(embodiment 16)

Figure 70. shockwave system safety cabinet, transport (left) and stacking and storing (right).(embodiment 16)

Figure 71. replaced using the quick liquid disconnecting accessory.(embodiment 16)

Figure 72. there is the image forming optics system schematic of the Automatic analyzer of robotics.(embodiment 1 and enforcement Example 9)

Figure 73. image forming optics system schematic Automatic analyzer.(embodiment 1 and embodiment 8)

Figure 74. the image analysis software of automation.(embodiment 8)

Figure 75. the bacteria Bacillus anthracis Lethal Factor Protein in people's whole blood is detected by automated analysis.(implement Example 14)

Figure 76. the software architecture of expansion.(embodiment 6)

Figure 77. the concentration deposition of the target of the mark of selection.(embodiment 2)

Detailed Description Of The Invention

Summary of the invention.The present invention is a kind of analyzer, and it is used for quick and delicately detects medical science, animal doctor, industry and ring Target in the sample of border.The present invention can test multiple sample types of many target types, including cell, virus and molecule. Detect and calculate the target complex compound of single marking after selecting in specific target using low magnifying power large area imaging, this Invention achieves its sensitivity and efficiency.Embodiment of the present invention can be by from the analysis with only several moving parts The multiple machine complexity of instrument is integrated in supermatic platform.The embodiment of automation can make user steps minimum Change, including sample preparation.The present invention can provide format high throughput test as needed, have automation sample input, process, Analysis and result report.Described imaging analysis instrument can be designed to and the title herein with September in 2009 submission on the 24th International application no for " Kits and devices for detecting analytes " _ _ _ _ _ _ _ _ _ _（It passes through to quote It is expressly incorporated herein）Described in kit or device be used together.Described device and kit can be used for herein and The international application of entitled " the Method for detecting analytes " of September in 2009 submission on the 24th Number _ _ _ _ _ _ _ _ _ _（It is incorporated herein by）Described in test.

Following partly in describe some key functions and the attribute of the present invention：

1. sample input

2. agent treatment

3. process container motion

4. manage input sample information

5. intermediate treatment

6. specific selection

7. it is imaged

8. graphical analysis

9. result report

10. post-process

11. systems control

1. sample input

Analyzer can include one or more sample input subsystems, they allow analyzers with one or more Sample interacts.Described analyzer can receive many different types of samples and Sample introduction pattern, and they can be supported The user job stream of wide scope.After adding analyzer, sample can also experience test pre-treatment.

The type of sample.The consistency range of sample can be from urine, excrement, blood, serum, saliva to mucus, food or Water.Using swab or wiper, from surface collection environmental sample, or can collect from air or water.Sample volume can be very big Ground change.Described volume can be, for example, less than 1 L（Blood is referred to for thorn）(Figure 26) to more than 1 mL（For wash-out Nose swab sample）(Figure 17).Described sample can pass through, or not through pretreatment.For example, it is possible to add them into Before analyzer, diluent or growth agents are added in sample, or before adding analyzer, sample grown can occur. Furthermore it is possible to one or more of additives are added in sample.Can before or after importing analyzer, by anti-coagulants plus Enter in whole blood sample, to prevent from condensing.Particular analysis instrument embodiment can be designed to process one or more specific samples.

Analyzer can receive the perhaps how different test type (Figure 38) of a special test type (Figure 33).Multiple realities Testing type can successively (Figure 33) or run close to mode (Figure 38) with random.Analyzer can store and manipulate for test Reagent, or described reagent can storage and manipulation (Figure 28) outside analyzer or in the experimental provision in importing analyzer.

Sample introduction.Sample introduction can include importing sample and be analyzed the arbitrary steps needed for instrument is processed.May deposit In many different feasible Sample introduction patterns.Sample can import analyzer (Figure 10 and Figure 17) by shuttle, or It can be straight by pipette, sample collection ball, swab, the finger with drop of blood, syringe, capillary, fabric or wiper Ground connection adds, to provide a small amount of example.Sample introduction pattern can be automation, manual or combination.Manual sample Product import an example as shown in fig. 7, wherein user by shuttle be placed directly in test pallet on processed.Manual and Shuttle as shown in Figure 28 and Figure 29, is wherein put into loading disk transmission by user by one combination of automation Sample introduction Band, it automatically enters analyzer here, and is processed.Figure 37 explain using automation sample tracking system completely from One embodiment of the Sample introduction of dynamicization.Here, shuttle is delivered to analyzer, wherein when fresh sample has arrived When reaching, optical pickocff can detect, and measure sample and be used for processing.This whole process occurs without user with interacting.

Analyzer can accept many different shuttle structures.The size of shuttle, form and content are permissible Widely varied, depending on purposes, sample type or analyzer form.Shuttle scope can be from having particular optical properties Simple open container（User executes many materials exchange step wherein）Multi-functional to the stream control part with automation Analyzer.Shuttle can be individual module (Figure 26) or stacking (Figure 20).They can also be single (Figure 31) or multiple Shuttle.Support can be entered in analyzer by acceptance, and described analyzer contains one (Figure 32) or multiple (Figure 27) sample and holds Device.Shuttle can be put in pending analyzer, in processing procedure, sample is retained in internal (Figure 29), or sample Product can take out from container and process (Figure 37 and Figure 38) different containers.

Analyzer accepts shuttle to carry out experiment process and there are various ways.Sample introduction can be simply to user sample Product container is placed directly in be analyzed on test pallet immediately, such as shown in fig. 7, or can complexity divide to as shown in figure 15 Analyzer, it uses optical pickocff, conveyer belt and three axle gantry robot.Shuttle input can use one or more Subsystem, they are moved using gravitational effects (Figure 22), linear promotion (Figure 24), robotics (Figure 15) or band (Figure 21) One or more shuttles or shuttle support.The outside automation cell not being combined with analyzer can also deliver Shuttle is processed to analyzer, such as automates tracking system, it can be independent hospital's sample tracking system A part.

Sample pretreatment.After entering analyzer, it is (anti-in such as contact blood collection tube that sample can experience pretreatment Solidifying agent).Sample or shuttle can temporarily be queued up, with etc. pending, or it can experience one or more pre- places Reason.Sample pretreatment can include but is not limited to：Heating, cooling, mixing, dilution, incubate, add additive or medium.Pre- place Reason can occur on shuttle automatically, or can be started by analyzer.

2. agent treatment

In order to analyze sample, analyzer may need to control the timing in example reaction stage.This potentially includes mobile reagent, Including liquid.The present invention can provide one or more of movements and measure the means of different reagent, and they can be included with essence The mode really controlling moves liquid, solid and gas.

The complexity of agent treatment analyzer subsystem can change.In the simplest situations, agent treatment is formerly Automatically metering and timing, such as Fig. 7 inside the shuttle entering.In this embodiment, analyzer does not need any reagent Processing function.But, in more complicated analyzer embodiment, such as Figure 39, many reagent add and process step by point Analyzer executes.Here, added by analyzer, mix and the multiple reaction reagents of timing, its effect is that sample is tested.

Being permitted eurypalynous reagent may need to control motion by analyzer.Need motion and the reagent of metering can include one Plant or more kinds of test reagent, diluent, eluent, additive, cleaning solution and waste liquid.

The agent treatment subsystem of analyzer can use reagent management method, and the execution of methods described is completely loaded at point Outside analyzer（off-board）, be completely loaded on analyzer（on-board）, or combination.Load outer（off-board） Agent treatment includes the analyzer shown in Figure 28, is wherein acted on by internal capillaries and automatically moves whole blood, and with Through the self-contained reagent reacting (Figure 26) in disposable shuttle.This analyzer embodiment mobile example container is carried out Imaging and result treatment, but it does not need any reagent processing subsystem.Or, fluid management can be completely by analysis instrument control System, such as in Figure 40, is wherein moved by rotation pipette robot and metering whole blood.By another pipette machine on analyzer People adds other reagent, to start to react.Mixing and reaction opportunity are also by the agent treatment subsystem controls of analyzer.At reagent Reason can also partly be managed by analyzer, such as in figure 21, is wherein opened by the mechanical actuator on activation analysis instrument Dynamic example reaction, but all other agent treatment step（Move including liquid, add reaction reagent sample to sample and mix Close）Occur inside shuttle.

Liquid moving method.Can various ways to be passively or actively, mobile liquid.The passive movement of liquid, permissible Realized by such as capillarity, and induced flow can be come by the surface tension interaction of molecular level, this fits For the situation in the slype of the analyzer that blood sample is inserted Figure 26.Other passive method for treating liquids include permeable pressure head （Such as across semipermeable membrane）Or pass through electrical environment difference, and other method.Flow of fluid in passage can be passive（? In the case of capillarity）Or active（If it is under an applied pressure）.

Active liquid movement requirement across liquid induced pressure gradient.There are multiple methods moving liquid in like fashion.Logical Cross the plunger in Figure 17, the screw of the shuttle in Figure 21, or directly linearly promoting by the analyzer of Figure 22, Ke Yizuo For fluid.By the deflection of Solids Analyzer（Such as in deformation film or diaphragm）Or bellows or accordion spline structure Collapse or expand it is also possible to move fluid.

Other instruments of Active liquid movement include blister pack, frangible seal and combination.Can be by hydraulic seal In blister pack, and to be discharged until it ruptures in deformable module by applying pressure to.Likewise it is possible to fragility is close Envelope is designed to crush in specified pressure, thus after certain force is had been applied to liquid agglomerate, mobile liquid.By roller machine Structure, can move the liquid reagent comprising in the blister pack sealing by frangible seal, such as shown in Figure 67. By reagent is packaged in module bag, it is possible to achieve longer shelf life and reliability.Can deposit being with or without bubble-cap In lower use frangible seal.The simplicity of roller mechanism may insure robustness.Controlled directed movement using roller-type mechanism Possibility can limit backflow and cross-flow, or even be used for mixing.Roller mechanism can be integrated in shuttle, or conduct Subsystem is placed on analyzer.Specific embodiments of this modular concept are illustrated in U.S. Patent number 5,254,479.

There are other active moving process of integrated mechanical movement.In some cases, mechanical action can open door, such as Valve.Valve has polytype, including such as throttling（pinch）Several example such as valve, rotary valve, check valve or duckbill valve.Other Mechanical movement, the expansion of such as deformable absorption base or extruding, can be moved with induced fluid, as liquid extrusion or crowded Enter sponge.There is special absorbability and multiple absorbing materials of capacity can be used for this effect.Another in mechanical movement is real In example, 2 physically separate component set being not adjacent in the past are combined together and align.

The other methods actively moving liquid include, and remove the solid of closed channel or liquid or gas on strategy.This The assembly of sample can be realized by movement, fusing or evaporation, and these pass through high temperature, chemical reaction, absorb or be exposed to radiation （Such as ultraviolet wavelength light）To realize.Shifted by direct liquid, such as pass through pipette it is also possible to physically mobile example. Figure 34 and Figure 37 shows liquid movement is carried out by pipette.Mechanical actuator can with shuttle on interface （Plunger in such as Figure 17）Interact.Mechanical actuator can include pin, plunger, hook, the shifting of hammer, roller or other surface Dynamic.By applying vacuum or pressure, such as pass through swabbing action, such as using syringe, peristaltic pump, vane pump or membrane pump, Can be with mobile reagent.

It is expected that any combination of one or more of above-mentioned moving methods can set up the liquid handling circuit of complexity Figure.One example as shown in figure 17, is wherein moved by analyzer activation liquid.Agent treatment subsystem is by linear actuator group Become, described linear actuator oppresses the plunger of shuttle cap, until sample and the grown cultures being included in shuttle Base interacts.Analyzer and then timing incubation growth specific time period.When the time after, linear actuator is oppressed further The plunger of shuttle, the liquid in mobile growth hole, to imaging hole, is automatically tested in shuttle.It is contemplated that To many alternative combinations of reagent moving method, to set up any number of uniqueness line map.

Flowing starts.There is many beginnings controlling reagent motion and the method on opportunity.Frangible seal, resealable Film or valve can stop fluid from moving before machine in due course.Can oppress or relax O-ring, to control flowing.In a specific way The assembly of the mechanically movable being fitted to each other, can be used for controlling flowing.Example includes but is not limited to：Hasp, screw or spiral shell Rotary drill, press-fit, hinge or slide plate.

Surface treatment be can be used for modifying flow performance, wherein imports to hydrophobic region or hydrophilic area including suction nozzle On analyzer sub-component.These regions can be set up by environmental treatment, such as sub-component is placed on oxygen plasma, electricity In dizzy, ionically charged room.Module can also be exposed to other types of process, including but not limited to, chemical etching, steaming Vapour and liquid deposition, teflon or other are not glued or low adhesive coating layer（Including other immersion coatings）.Selected by material and process, Including superficial makings and roughness it is also possible to realize beginning and the direction of flowing.

The reversible coating of light can be used for setting up such surface, its feature（Such as hydrophily or hydrophobicity）Can basis Need and change.

Metering fluid.Accurately fluid can be measured, and be delivered in one or more parallel or continuous container. By one or more analyzer subsystems or sub-component（It includes many passive and active method）, metering can be controlled.

Fluid can actively be measured in many different ways.Active fluid metering can include mobile plunger, syringe or Piston, with or without roller compressing blister pack, the rotation of the controlled rupture of frangible seal, auger or screw, make film, tabula Film, bellows or the deformation of accordion spline structure.By pipette it is also possible to direct transfering fluid.

Passive metering can be occurred with several method.Can by geometry designs partially or even wholly control sub-component or Shuttle, described geometry designs compensate flow resistance, for example, pass through surface tension or pass through capillarity.Thin by diffusing Water or hydrophilic frontier district is it is also possible to be measured.In this case, liquid displacement gas or air, but can not at it The hydrophobic membrane easily passing through or boundary stop.Another passive embodiment can include, using the metering of vacuum fill area. In hole or container, self-contained vacuum can open to fluid volume, and described fluid volume is pushed back by higher pressure, such as greatly Air pressure.Border between release region of no pressure and liquid, can lead to a special liquid volume, it pours to balance with liquid Low-pressure area, be measured into before the region that vacuumizes.Same parts for accurate measurement can be used for timing.

Prevent from revealing.Described analyzer can have for liquid containing and prevent the part revealed.This can include hole, Container and passage and other receiving module.Accommodating flow of fluid can be by solid, liquid or gas with the border preventing from revealing Make, it controls the physical location of sample and motion path.

Exist many before pre-processing and measuring reactions steps, during and the method that prevents from afterwards revealing.Motionless Solids hold includes but is not limited to：Passage, hole, container and room（Including suction nozzle and ball）.There is also mat or film.Fluid is permissible For accommodating another kind of liquid, such as pass through focused flow（focused flow）, the emulsion of 2 kinds of Immiscible fluids or suspension, As several examples.These liquid can be static or motion.Flowing can be held by the solid components of mechanically movable Receive, described part can be included by hasp or press-fit, screw, hinge, slide plate, o- ring, valve, frangible seal or can be again The film of sealing and 2 parts fitting together.

Fluid may need to replace the air of retention；Method for exhausting therefore can be included to make retention in hole or passage Gas minimizes.There are multiple methods discharging air.Several examples include the films such as hydrophobic membrane, vacuum or low-pressure area, another kind Liquid, gas or deformable solid body（Such as diaphragm, capillary or the macropore leading to air, or porosu solid, such as organic Silicon）Displacement or extruding.

Neutralize after it terminates it may be necessary to make cross-flow or backflow minimize in metering process.Using film, valve or bubble or not Miscible fluid, the such as oil containing aqueous sample, or liquid plug, can anti-backflow.By thoroughly washing between samples Assembly, such as suction nozzle and reaction cup (Figure 40), can make cross-flow minimize.

Mixing.Described analyzer can have the part for fluid-mixing and other liquid or dried reagent.Mixing can To be passively or actively generation.Passive mixing can such as will with including the mode such as low-yield of turbulent flow, rotating path or solution Liquid adds in dried reagent.Actively mixing can include but is not limited to, physical motion, such as rotates or vibration oar or stirring (such as imbibition up and down), vibration such as ultrasonic wave are beaten in rod, repeatedly suction, import bubble, or by vortex or nutating.In analyzer In can include one or more of mixed methods.

3. process container motion

Container motion can be realized with polytype.Container can be have outside liquid motor function simply single Unit, or there is the somewhat complex design of the closing of fluid management and reaction basic structure, it is designed to need the outside fluid that starts to turn Move.In analyzer, process container motion can be linear, random, no or motion combination.In fixing process unit Model (Fig. 7) in, user is placed on container in the region specified, system will move processing subsystem (For exampleCamera, magnetic Body), container remains stationary simultaneously.There is the linear motion system executing series of processes operation with multiple directions.Figure 11,14,21, 22 and 24 use linear series to process model.Sliding platform is sometimes referred to as estrade it is also possible to execute continuous or random process Function.Figure 14 shows platform subsystem.

Rotary motion includes carousel.Carousel can be used for saving surface area or assembly（Such as motor） The occasion of number.It can be continuous or random that carousel is processed, and is characterized in Figure 28,30 and 35.In them Some are used for liquid handling in combination.

Needing occasion close at random, it is possible to use several movement combinations.For example, cartesian coordinate robot is (dynamic The grabbing, carry of power, vacuum carry or other container link model in), pick up put humanoid robot (carry in the grabbing, carry of motorization, vacuum or In other container link models) design can provide motor function.Figure 15,42 show random close to robot.There is random fortune Dynamic alternate design, such as serpentine band（As the main movement device with reversing ability）And transfer device（For mobile master Telecontrol equipment）Combination.

The transfer of other types of container and can process and holds between motor element, between motion and processing function unit Mobile container between device.These models include slope, actuator, trap door, spring guide, the design of gravity cover.Figure 15,20, 23rd, 24,29 in the design of their mobile container using one or more metastasis models.

4. manage input sample information

One importance of the present invention is the management of input sample information.This includes experimental subjects information and experimental analysis The management of information.

Experimental subjects information provides the ability being associated experimental result with experimental subjects.For example, in clinical application, this Invention provides the mechanism associating experimental result with patient.In addition to TIME CORRELATION EXPERIMENTS object and result, experimental subjects information The excessive data relevant with experimental subjects can be provided.For example, in urgent surge test occasion, this systematic collection can be passed through Patient's contact and historical information, to promote the patient care of next stage.

In addition to management misconduct object information, embodiment of the present invention can with management misconduct analyze information, it be with The relevant information of experiment itself.Experimental analysis information includes the type of experiment carrying out（Single or a plurality of）And it is relevant with experiment Analytical parameters such as control information.

Experimental subjects information.There are multiple embodiments for management misconduct object information.The embodiment warp using The workflow being often dependant on purposes and being suitable for this purposes.In the paragraph that some possible embodiments are described below.

One example is to manually enter experimental subjects information.Manually enter and can include:Subject data is write by user On recording card, data is electronically inputted laboratory information system (LIS) or hospital information system (HIS) by user, and makes Subject data is inputted instrument by the terminal with front panel, connecting or other mechanism.

In many purposes, there is the identifier of the experiment being produced by usual workflow system or patient-specific. This is used for tracking test result by usual data management system.In the embodiment supporting these purposes, test and test Result is associated with usual identifier, for report to usual data management system.This association can come real in many ways Existing.

A kind of mode that usual identifier is associated with experiment is to add it in experiment input pod.For example can be Bar code or hand marking are placed on sample tube or experiment cylinder.

The scheme of another tracking test result is, usual identifier is related to the identifier on input sample container Connection.For example, input block can have identifying device installed in factory, such as bar code.This input pod identifier can To be associated with usual identifier.This can be by reading or scanning identifier store them in many ways and realize, institute The mode of stating includes：It is stored on instrument, is stored on input pod, and be stored in Third party system.

Input block identifying device and usual identifying device can be using many identifications and identification reading technology.This can be One or more input blocks identify any combination of reading technology and one or more usual identification reading technology.Read Technology includes but is not limited to：Optical scanner and change into electronics ID form, optical scanner and change into image format, radio frequency is swept Retouch, noctovisor scan, and read by hand and by keyboard/pointing device or sound interface input.

At the end of experiment, result is associated with usual identifier, and reports to usual data management system.This can To be automatically completed by instrument.For example, instrument can be communicated with LIS/HIS system.

As the replacement scheme of the tracking test result of the usual identifier producing, some purposes can be using analyzer There is provided mechanism, with TIME CORRELATION EXPERIMENTS and patient.For example, when the potential source biomolecule harm testing big colony exposes, analyzer can be remembered Record patient information, and the contact between information and laboratory sample is provided.There are many schemes that experiment is associated with patient.They Including：Capture patient information, makes patient contact experimental result, provides identifying device to patient, and the combination of these schemes.

Capture patient data can be realized in a variety of ways.They include but is not limited to：Input number on the dash panel According to, input data on web browser or other additional thin customer interfaces, defeated on the direct or computer of network connection Enter data, using sound interface system input data.

There is the identifying device that many can be supplied to patient.Identification article, such as label, card can be provided to patient Piece, wrist strap.Beeper can be provided to patient or allow to carry out other sender units of signal transmitting by unique code. Every kind of such device has identification mechanism.Possible mechanism includes：Textual identifier, bar code, radio frequency identifiers (RFID) And bluetooth.

After experiment terminates, experimental result is associated by system with patient.Then using selected sender unit to trouble Person signals, and notifies patient based on the suitable next stage treatment of result using unique code.The example embodiment party of this process Case includes：

The telephone number providing in patient information, by phone, using people or interactive voice response (IVR) contact. Patient's next stage is notified to treat.

According to the address providing in patient information, by SMS text or instant messages, enter pedestrian or interconnection, with logical Know that patient's next stage treats.

By wearable device positioning function, positioning is individual, then provides the direct people with regard to next stage treatment to consult Ask.

On the sender unit providing, call patient.Notify the suitable case control personnel of patient's contact.

By notification system, notice patient's name or ID.Notify the suitable case control personnel of patient's contact.Notification system Sound, the sound amplifying and identifier display can be included.

After collection sample, patient moves to waiting area.Carry out successively with test, they are waited in line.Read in output station Take patient's ID device.It is then based on experimental result, notify patient's next step to treat.

After being tested, patient coupled system personnel.They are apprised of result and next stage treatment.

Based on their identifier, patient can be electronically close to result.

Can be using any combination of 2 or more such schemes.

Experimental analysis information.Analytical instrument as embodiment of the present invention accepts and explains relevant with input sample Information, how to process and analyze the information of sample to provide.This includes the type of experiment carrying out（Single or a plurality of）, school Positive information and the other analytical parameters relevant with experiment.

Input sample can be with experimental analysis information.From input sample information can as machine-readable form from Input unit is retrieved, described form such as 1D bar code, 2D bar code, other optical form, magnet readable tag or radio frequency Identifier.It can also be manually entered by user.Correction and analytical parameters information are usually as a part for production process Produce.It can be directly applied sampling device.Another embodiment is offer identifier on sample, and it is connected to and carries For on the independent medium of information.This medium may refer to one or more samples, and can be arbitrary people or machine readable Form.

Described system can provide mechanism, for differentiating which experiment carried out in each input sample（Single or plural Individual）.In many embodiments, the present invention retrieves input pod identifier first by one of said mechanism, and then calculating will The test set running.The embodiment being possibly used for this process includes：Run single experiment type, using fixing experiment class Type code, using the experimental code loading criticizing combination with shuttle, and in external system（Such as LID/HIS）In find Experiment type.

One embodiment once can process only single experiment type.In this case, the type of experiment to be run Only determined by instrument.

Instrument can also be using fixing experiment type coded system.In this case, directly retrieve from input pod Experiment type.

One embodiment can also the Experimental code system that can load of use.Before running experiment, will be with regard to experiment Information scanning or input in instrument.This sets up new experiment code and relevant information carrys out running experiment.This new experiment code Can encode on input pod.

The Experimental code scheme that this can load is worked together with being criticized with sample, wherein batch card（lot card）Or its Its device is transported together with shuttle group.By batch card scan or input in instrument.This sets up batch identifier and has The experiment parameter closing.These can include experiment type, control information, failure period and analytical parameters.Each sample in batch Container is encoded with batch identifier, and when sample is processed, described batch identifier is read by instrument.Instrument can use this mark Know symbol to consult lot data, and retrieve experiment type and other parameters.Batch tabulating equipment can also provide security.At this In the case of, batch card data is encoded into, only authorized batch card is accepted.Only relevant with authorized batch Experiment just can run.

In some embodiments, from the usual identifier with input sample container combination it may be determined that experiment type.When When processing experiment, read usual identifier as mentioned above.This identifier can be used for consulting experiment type and other experimental analysis Information.This information can be previously entered in this system, or from management system（Such as LIS/HIS）Electronically retrieve.

5. intermediate treatment

Before specific selection and imaging occur, analyzer can promote intermediate treatment.Intermediate treatment can simply extremely Wait and carry out example reaction in 10 minutes, or it complicated can extremely add antibiotic and growth agents, little in 37 DEG C of high temperature incubation 4 When, it is subsequently adding the transmitting of reagent signal and selected section, with ultrasonic mixer mixing, and in other 5 points of 25 DEG C of incubation at temperature Clock, then carries out specific selection and imaging.Intermediate treatment is important, because some tests need extra test procedure, Such as grow or incubate, to distinguish positive and negative sample.For example in MRSA diagnostic test, there iing such as methicillin Positive and negative sample can be distinguished Deng the bacterial cell growth in the presence of antibiotic.

Embodiment can include different subsystems, and they provide environmental condition that carefully control and maintenance.This can To include, add in one or more time points or remove the reagent of liquid, drying or gas form, diluent or interpolation Agent, maintains one or more samples in one or more temperature or humidity range, provides stirring by motion, or guarantee not There is stirring special time period.Middle subsystem can include the assembly for cell growth or nucleic acid amplification.It can also wrap Include the dress of one or more blenders, agitator, aerator, oscillator, heating or cooling element, queuing and mobile example Put, timing and the device controlling sub-component and sample.The subsystem of intermediate treatment can include allowing one or more samples The part of the mobile subsystem specific times that come in and go out.Described subsystem may be embodied in the specified humidity of 0-95%, or it can be at any time Between change.Similarly, temperature range can be from less than room temperature to more than 37 DEG C.Temperature in subsystem may remain in static Temperature, or it termly can change in one of multiple temperature or temperature range.For example, the detection (Figure 43) of MRSA may need To incubate 4 hours at 37 DEG C, wherein stirred sample, and provide enough nutrients and enough inflations for cell growth（With Allow aerobic respiration）.

Temperature can be controlled with any number of approach.By resistance heater or Peltier device（It can be used for Heating and cooling）And the material for manufacturing subsystem, temperature can be affected.These assemblies can be integrated in analyzer, Or may be embodied in the external modules such as shuttle.For example, when needing quick temperature conduction, subsystem can be by Copper becomes, or it can be by insulator（Such as PVC foam）Formed, so that heat transfer time minimizes.By be internally integrated Probe, can be with monitoring temperature.The control of the time of staying of the sample in intermediate treatment subsystem, can be from manually timing Those are to continuous those (Figure 29 and Figure 30) queuing up at random close to those (Figure 42) queuing up.

6. specific selection

Analyzer can provide one or more subsystems, for the specific target in Selection experiment sample.Specificity Selection can be useful because it can drastically reduce unconjugated mark in the sample area that will optically inquire about and The background signal of the mark non-specifically combining.Selection can also be favourable, because it can be by all target signal section Complex compound is divided to be collected into optimal ad-hoc location and direction for imaging inquiry.

There are many different types of specific selections.Certain methods can include, and capture is with bound fraction（For example, Antibody or oligonucleotides）On coated surface.Magnetic force can be applied on sample, wherein the physics of magnet assembly and field property Lead to movement in shuttle for the target part combining.Can by target part be designed with some for magnetic selection For optimal magnetic susceptibility.Magnetic selects to utilize one or more electromagnets in specific direction or solid magnets.Example As ferromagnetic for one or more solid-state neodymium-boron-rod being placed in parallel (Fig. 3) adjacent to each other, or be imaged with permission, together The spacing that Shi Fasheng selects places (Fig. 4).Other structures, such as, but not limited to, one or more disks, spherical and cylinder Shape (Fig. 5) magnet assembly can be used for specifically selecting target part.In some cases, sample can be with target part Capture is compatible, and described target part is rapidly formed uniform individual layer.Other types of selection can include gravity（Such as it is centrifuged Or sedimentation）, buoyancy, optical challenge（Such as fluorescence, chemiluminescence）, morphology or white light microscopy).Other methods include but It is not limited to：Diffusion and size exclusion, for example using film or filter those.One or more such method can be at single point It is used together or separately in analyzer.

Analyzer can have selection subsystem, wherein pass through directly projecting on detection zone, select the sum in reaction In conjunction with sample in target.Volume directly linearly projecting from the teeth outwards, can strengthen the imaging inquiry of test.For example, exist (Figure 66), in, the reagent including magnetic and fluorescence particle pulled down to bottom hole and forms single conforming layer, and they here may be used With from following imaging.It is also envisioned that other embodiments, substitute on surface including choosing, such as side or top surface.Select Can carry out under not flowing.

7. it is imaged

Analyzer has a subsystem, and it includes the image forming optics with photodetector array, and it can be low Magnifying power obtains wide region.Low magnifying power width region is constrained to as the sensitive and quick detection of the target in sample It is important.Analyzer imaging subsystems can be imaged to whole test specimen, has as little as one image.Imaging subsystems bag Include the device for irradiation, detection, image adjustment, Image Acquisition and photodetector array.

Imaging subsystems can include the device for irradiation.Irradiation can include but is not limited to, incandescent lamp bulb, laser Or light emitting diode (LED).One or more of every kind of light source can be included.In some cases, it is possible to use many Individual irradiation bomb is increasing the intensity of the excitation energy in the specific region of image detection.Irradiation bomb can be broad band (wide scope Energy wavelength) or specific wavelength source.Before or after they are irradiated on sample, irradiation bomb may be adjusted or without tune Section.In certain situations it is desirable to such as chemiluminescence, for example, no irradiation.Chemical reaction induction can be with the visual energy of direct detection The transmitting of amount.Before obtaining image by photodetector array, image can be adjusted to strengthen the resolution ratio of image.Can adopt Use optics（Including lens, diffraction gradient and wavelength filter）To adjust image.Lens can focus on or out-of-focus image, makes During its arrival photodetector array proper, it amplifies less than 10- times from actual size.Lens can also transmission figure picture, correct color Difference, coma（coma）Or other optical effect.Wavelength filter can block the light of some wavelength, and allows other wavelength to wear Cross.Filter can be used for exciting launch wavelength or the two on.In some cases it is not necessary to the regulation of image.

By using one or more photodetector arrays, carry out Image Acquisition.There is many different in like fashion The method of capture images.Photodetector array can include but is not limited to：Charge coupled device (CCDs), photodiode or Avalanche photodiode array (APDs), single-photon avalanche photodiode (SPAD) array, photon multiplier tube (PMT) battle array Row or complementary metal oxide semiconductors (CMOS) (CMOS) array.The price of photodetector array, resolution ratio and sensitivity wide cut become Change, and can be selected for different performance characteristics, this depends on the test requirements document to analyzer.

Imaging subsystems can include the focusing arrangement for obtaining image.This can include passive approach, such as physics Geometry (such as v- groove or alignment pins) or the automatic aggregation algorithms of head such as software (for example focusing on reference mark), Laser distance sensor (such as Keyence) or physical distance sensor (Hall effect probe), as several examples.

8. graphical analysis

The major function of graphical analysis is, the amount of signal present in the quantitative image producing in imaging subsystems.Analysis Output is determined for experiment, the feature of container.For example, it is the basis of experiment refusal（When invalidating signal）, or it can To detect inhuman readable code or the reference mark for container validity check.

Graphical analysis can contain the steps such as pretreatment, Signal separator and signal quantization.

Imaging Preprocessing Algorithm can be optionally applied to image.There are multiple Preprocessing Algorithm, including for example:

- target area (ROI) detection can be carried out, subsequent analysis is limited to the image-region containing signal.Deposit In multiple ROI detection schemes.These include：Using the fixing ROI based on consistent Image Acquisition mechanical part, examined by edge The calculating of cls analysis, searches known signal element（Such as it is imaged bore edges）Coupling filter analysis, the base on image Fiducial mark note or other known mark, and detected with threshold value and connected com ponents analysis.

- field can be flattened（Field flattening）It is applied to image, to adjust uneven luminous effect.

- image processing function of many standards can be applied.These include：Smooth, sharpening, rim detection, contrast increase By force, the filtration that lower noise, sequence filtration, average filter and mate, to find signal or to remove noise or fragment (Oppenheim, A., Schaefer, R., Digital Signal Processing, Prentice Hall, 1974).Distortion correction algorithm can be applied, to adjust the known distortion effect being produced by imaging system.

In addition to strengthening input picture, which subsequent treatment algorithm pretreatment may decide that using, or determines that image is wrong Condition by mistake, such as lacks input, the input blocking, the shuttle of no illumination and breakage.

Second general graphical analysis element is Signal separator.This process removes the back of the body from the consideration of signal quantization step Scape, noise and fragment assembly.Possible Signal separator scheme includes：

Some algorithms do not use Signal separator.For example, simple algorithm is permissible by all image pixels that simply add up Generate result.

Some algorithms use one or more threshold ranges, only consider the picture with the value in one of described scope Element.

Some embodiments use above-mentioned Threshold Analysis, then the analysis of being attached property, and neighbouring pixel is combined In blob.Measure different blob parameters, and be based on those parameters, so that signal blob is separated with other blobs.For example, it is possible to To have very large-area blob and be regarded as fragment, and not be counted as signal.

Last general pattern analysis element is signal quantization.This analysis uses the output of Signal separator, and produces numeral , binary or calculating result.There is multi-signal quantization scheme.These include:

Some algorithms add up the intensity of all signal pixels, generate result.Summation can directly return.Summation can also be by Amplify, compare threshold value, or otherwise process, to generate final output.

Some algorithms are the statisticses based on individual signals component.For example, result can counting based on signal pixels. Or, if using connected com ponents analysis in Signal separator, result can counting based on signal blob or statistics, such as signal Blob intensity or the summation of area.

In addition to processing single image, graphical analysis can generate result using multiple images.This can be used Statistic processes, such as averages or median between images.Many image procossing can also expected difference in detection image. For example, the signal particle magnetically marking can move in the presence of magnetic field between framework.In this case, parser Signal component can be separated using the motion between framework.

9. result report

Analyzer embodiment can provide the device for reporter assay output data.Data include with experimental result, Experiment parameter, the patient for the treatment of, patient medical quality control data, correction and skillfully relevant key element.Needs according to user With the ability of analysis system, experimental result data can include " through-failure " designator, image and partly processing data. The display of data can take many forms, and including simple alphanumeric, it is shown in the vision being integrated in analyzer and shows Show device (For example,LED), integrated system display（Such as LCD）, or be there is the thin client of the web browser being connected with system On.In some designs, the NetPC Network PC of connection runs thick client applications.Except these are volatile, regard in real time Feel that beyond display, design can also integrated print option；Integrated loading, by common communication connection (serial port, usb, with Too net, firewire) in outside, and they can be to carry out record by the medium of physics or radiation to keep.Figure 13 is tool Have for showing the integrated printer of result and the analyzer of LCD.For longer-term record keep, can periodically by data with Ad hoc structure（Including database）It is stored on disk or other medium, access for later.These data can also be with any Form be sent to other business systems (For example,LIS, HIS).Finally, any or all data can be with any or all carry And design and form reported.Figure 25 shows the system with database, which show system control panel, the number of loading Control link, network interface and the interface with LIS according to storehouse storage, special commend ad.

10. post-process

After sample is by imaging and analysis, analyzer embodiment can execute one or more post processing steps Suddenly.Can be post-processed, to prepare another sample to analyzer, protect users from the material of biohazard, or pass through Eliminate user steps to strengthen the user friendly of analyzer.

Analyzer can execute one or more effects, to prepare next sample.These can include cleaning, waste Process or mobile one or more samples, reagent, assembly or container.Cleaning action can include, and rinses one or more Suction nozzle (Figure 46), imaging or reaction cup (Figure 47).Waste processes the accessory substance that can include removing and save as operation test The liquid wastes (Figure 48) being formed, or it may refer to for unitization shuttle to move to dry waste treatment box or appearance Device (Figure 16).Waste disposal container can be with or without either manually or automatically perception, and it allows user or analyzer Determine the time needing to change waste canister.Waste canister or accessory substance can provide visual cues (Figure 13), and they need to use Family interacts and to be cleaned, or they are likely to be of automatic perception analysis instrument, such as optical pickocff (Figure 38), when need When removing waste, it can be with analyzer or telex network.

In many embodiments, post processing includes the preparation of another sample determination.This can include washing and clean Assembly already mentioned above, but be likely to including reset or guide sub-component positioning (Figure 14), supplement reagent volume (figure 49) and moving assembly or shuttle depart from imaging subsystems (Figure 13 and Figure 15).

11. systems control

In order to execute and report analysis test, analyzer can have the image detecting for control system and analysis Device.This function is provided by system control component.It can be used for controlling and coordinate all activities of system.Can be by system control The function that system provides includes but is not limited to：Instrument controlling, motion control, liquid handling control, incubate control, illumination and image Obtain control, course of reaction timing, scheduling of resource, user interface, data input, system mode show, system architecture and control, System maintains and diagnoses, result shows and exports, data management is communicated and image with external information management system (LIS/HIS) Analysis.

Typical instrument controlling realization can execute such as identifying in Fig. 9 and 25 of task, controls motor, actuating Device, pump, timing and motion, mixing, display and PERCOM peripheral communication update (For example,Button is pressed, mouse is clicked on), subsystem testing And diagnosis, data storage, analysis and retrieval.According to the needs of special-purpose, these basic tasks can be with other task phase groups Close.

In many embodiments, system controls and is made up of microprocessor or other computing unit.This can include non-easy The property lost storage capacity, system interface circuit and system controlling software.Embedded processor module and interface circuit are commonly located at list On individual circuit board, but can be arranged on multiple plates.Electrical interface between system control subsystem and other system component One or more passages of two general purpose industry and custom interface can be included.The general standard using includes standard and leads to With universal serial bus (USB), IEEE 1394,10/100 base T Ethernet and RS-232 standard serial interface.Using custom interface In the case of, control system often provides low-level assembly to control.For example, system controls and can include motor controller, its With the motor interface with simulation step motion control signal.

System control subsystem hardware can be based on the general purpose computer of business.This can be arranged to the thing of all inventions Reason integrated package, as single special cell, or is provided by user.Electrical interface from general purpose computer can be One or more industry standard interfaces connect.It can also be connected by the customization that subscriber card provides, and described subscriber card adds To on general purpose computer.When embodiment uses general purpose computer, it can be come directly using standard interface It is connected on system element.Furthermore it is possible to exist and the docking of integrated circuit.

System controlling software can provide logic, and it executes system control function listed above.System controlling software can To be made up of 4 or more elements, they can include executive component, system service, data management and user interface.

System controlling software can have executive module.Described executive module can provide core logic, its control system Run time activity.The possible embodiment of execution component software includes but is not limited to：The control directly encoding is patrolled Volume, event handling state machine, script drive system, general purpose script, customizing script language, and possible execution bag Include one of they or more kinds of combinations.

There may be the software systems service of one group of management nextport hardware component NextPort of the present invention.In addition, most software ability be by System service provides.System service includes but is not limited to：At motor and sensor management, camera control and interface, liquid Reason management, mixed cell management, bar code elements interface, database interface, utility program and graphical analysis.

System controlling software can include data management.Data management element can be responsible for following with pending, during and Relevant information is tested in the analysis completing.

User interface can be included in system controlling software.User interface element can drive multiple displays and user defeated Enter mode.These include but is not limited to：Front panel shows, additional thin customer interface such as web browser, additional thick visitor Application program that family interface is run such as on the network being connected with personal computer, printer output and with such as hospital letter The interface of other analyzer such as breath system (HIS).

Embodiment

With regard to following non-limiting embodiments, further describe the present invention.Unless otherwise noted, special in an embodiment Any element of the not analyzer of description is commonly used for the analyzer of the present invention.

Embodiment 1. is imaged.

General introduction.Each embodiment of analyzer has the subsystem of the imaging of execution test.With having optics Photodetector array obtains image, produces the image that magnifying power is less than 5X.In most of the cases, enlargedly carry out without any Imaging.Imaging is favourable for quick sample processes and analyzes, because it has wide dynamic range.By making to surpass Cross the same detection system of tens thousand of target developments, the sample with only one or two targets can be analyzed.Wide region is low to put Big rate imaging can eliminate complexity and the cost of precise optical device.It also eliminates the complicated approach detecting whole sample, all As scanning.Analyzer imaging subsystems can detect whole test specimen with as little as image.Imaging subsystems include for Irradiation, detection, image adjustment, the module of Image Acquisition and photodetector array.

The analyzer optics not automated.The analyzer (Fig. 8) not automated uses the imaging subsystem shown in Fig. 7 System.In this case, imaging occurs in the upper surface of imaging hole.Using CCD photodetector array (Sony XCD SX-910) To execute the imaging do not amplified to large sample target region.2 LED of arrangement (Luxeon transmitter 3W LED- Blue, Lumileds, LXHL-PB09) focusing on sample, as shown in Figure 7.Each LED component is by the constant electricity of 1 LED, 1 LED 1A Stream power supply (Future Electronics, 3021-D-E-1000-LF), 1 LED condenser lens (focal length=50 mm, PCX, Edmund Scientific, 45-361), 1 LED pointing instrumentation lens (Lumileds, LXHL_NX05) and 1 LED emission filter (Chroma, Z475/49X) forms.Launching light from sample is no amplified 1:1 relay lens (Edmund Scientific, 45-760) collects, and carries out spectrum tune by launching filter (Chroma, HQ535/50m) Section.

Complete focus adjustment with hand.User using have thin pitch regulated screw linear course slide block (Newport, AJS-02H) image is adjusted to focus.The mechanical tolerance of imaging hole and guarantee imaging hole target in the movable length of vertical stroke Thing is in the range of optical system depth of field.As described in Example 3, calculate graphical analysis.

The analyzer optics of automation.The analyzer (Figure 14) of automation is using imaging explained in Figure 73 System.In this case, there is the basal surface in imaging hole in imaging.Using CCD photodetector array (Sony XCD SX- 910) executing the imaging do not amplified to large sample target region.4 LED of arrangement (Luxeon transmitter 3W LED- Blue, Lumileds, LXHL-PB09) focusing on sample, as shown in Figure 73.Each LED sub-component is constant by 1 LED, 1 LED 1A Current and power supply (Future Electronics, 3021-D-E-1000-LF), 1 LED condenser lens (focal length=50 mm, PCX, Edmund Scientific, 45-361), 1 LED pointing instrumentation lens (Lumileds, LXHL_NX05) and 1 LED emission filter (Chroma, Z475/49X) forms.Launching light from sample is no amplified 1:1 relay lens (Edmund Scientific, 45-760) collects, and carries out spectrum tune by launching filter (Chroma, HQ535/50m) Section.

By the mobile combination unit of imaging platform described in embodiment 8, complete focus adjustment.Fig. 2 shows from allusion quotation Type measures the image of capture.As described in Example 3, calculate graphical analysis.

Surge test analyzer optics.Surge test analyzer (Figure 15) is using the imaging explained in FIG Subsystem.In this case, there is the basal surface in imaging hole in imaging.Using CCD photodetector array, (2M pixel CCD is shone Camera, uEye, UI-2550-M) executing the imaging do not amplified to large sample target region.(Luxeon sends out to arrange 6 LED Emitter 3W LED- Blue, Lumileds, LXHL-PB09) focusing on sample, as shown in Figure 72.Each LED sub-component is by 1 Individual LED, 1 radiating piece (Aavid Thermalloy, 374124B00035), 1 LED 1A constant current power supply (Future Electronics, 3021-D-E-1000-LF), 1 LED condenser lens (focal length=50 mm, PCX, Edmund Scientific, 45-361), 1 LED pointing instrumentation lens (Lumileds, LXHL_NX05) and 1 LED emission filter (Chroma, Z475/49X) forms.Launching light from sample is no amplified 1:1 relay lens (Edmund Scientific, 45-760) collect, and spectrum regulation is carried out by launching filter (Chroma, HQ535/50m).

By in each loopy moving camera module apparatus, completing focus adjustment, as shown in figure 57.To have integrated putting The closed loop stepping motor (Oriental Motor, AS46A) of big device is connected to vertical linearity axle (Deltron, DL26L- On 70-ST-C-PH), with mobile imaging system, make it lift imaging cup and leave the fixing distance of optics.Cup and imaging The mechanical tolerance of unit is less than the depth of field of optical system.As described in Example 13, calculate graphical analysis.Figure 63 shows from allusion quotation The image of type test capture.

There is the analyzer of the automation of robot optics.This Automatic analyzer (Figure 48) uses and solves in FIG The imaging subsystems released.In this case, there is the basal surface in imaging hole in imaging.Using CMOS photodetector array (Mightex BCN-B013) is executing the imaging do not amplified to large sample target region.Arrange 6 LED (Luxeon transmitters 3W LED- Blue, Lumileds, LXHL-PB09) focusing on sample, as shown in Fig. 1 and 72.Each LED component is by 1 LED, 1 LED 1A constant current power supply (Future Electronics, 3021-D-E-1000-LF), 1 LED focus on thoroughly Mirror (focal length=50 mm, PCX, Edmund Scientific, 45-361), 1 LED pointing instrumentation lens (Lumileds, LXHL_NX05) and 1 LED emission filter (Chroma, Z475/49X) composition.Launching light from sample is no amplified 1: 1 relay lens (Edmund Scientific, 45-760) is collected, and is entered by launching filter (Chroma, HQ535/50m) Row spectrum is adjusted.

By the mobile combination unit of imaging platform described in embodiment 14, complete focus adjustment.As embodiment 3 institute State, carry out Image Acquisition and analysis.

Result.Fig. 2 and 63 shows the typical image from imaging subsystems capture.Embodiment 4,8,9 and 14 is explained Detailed experimental technique and result.

Conclusion.This example demonstrates several embodiments of imaging subsystems, described imaging subsystems are included for spoke According to, detection, image adjustment, the module of Image Acquisition and photodetector array.It is allowed for the low amplification of quick sample process Rate is imaged.

Alternate embodiment.There are multiple alternate embodiment, including those listed in detailed description.Can use Avalanche photodiode array or photomultiplier tube array replace the CCD device in the present embodiment.Light source can be xenon lamp, or It can be the lasing light emitter defocusing.Relative focal length and the depth of focus can be changed using different lens.Furthermore it is possible to change Excite and launch wavelength, to adapt to different spectral regions.

Embodiment 2. magnetic force.

Device can include the subsystem of one or more targets for selected marker, and this passes through to select power to apply To realize on the target-selected section complex compound of the mark in sample.Present embodiment describes several enter for applying magnetic force The method of row selection.By using producing magnet type and the structure of high magnetic gradient, it is possible to achieve the particle magnetically responding Magnetic select.Rare earth, solid magnets such as neodymium-iron-boron magnet can produce high magnetic gradient, is cheap, and can be used for this Many embodiments of invention.

The magnet structure (Fig. 3-5) of different magnetic field and generation field can be used for selecting the particle of magnetically response, and They are deposited in detection band.The different imaging hole using is solved using structure on the different embodiments of the present invention Geometry and imaging subsystems.

Parallel bar magnet combination unit (Fig. 4 .) allows to select with fixing arrangement simultaneously and be imaged.This can reduce the present invention The overall size of some embodiments, because imaging and magnetic subsystem may be positioned so that coming in close proximity to each other, and does not need to move To change between these subsystems.

Description.By 5 22x22x100 mm neodymium-iron-boron magnet (N50 level, Dexter are assembled on aluminum frame Magnetics so that N-S polarity is gradually rotated 90 ° between magnets (viewgraph of cross-section, Fig. 3), produce bar magnet combination unit (Fig. 3).The magnetic field line that this structure produces generates the magnetic gradient vertical with magnet combination apparatus surface, and (cross section of magnetic field line regards Figure, Fig. 3).The magnetic that the magnetic gradient producing can be rapidly selected in combination unit solution above selects particle, and by it Be uniformly deposited on the imaging surface parallel with combining the unit surface.

Produced parallel using 3.35x0.125x0.25 inch Nd-Fe-B bar magnet (N50 level, Dexter Magnetics) Bar magnet combination unit (Fig. 4 .), the 88x15x127 mm that described bar magnet is bonded at customized production has in the aluminium frame of lip The groove of interval 10 mm in.Combination unit is designed to the commercially available 96- and 384- hole microtiter of adaptation standard Plate.In the specific in the hole generation magnetic gradient of 96- or 384- hole microwell plate, (cross section in the magnetic field in hole regards described structure Figure, Fig. 4 .).The magnetic that the magnetic gradient producing can be rapidly selected in combining the unit solution above selects particle, and will They are uniformly deposited on the bottom (detection surface) of microtiter plate hole.

Using 1/16x1/4 inch Nd-Fe-B cylindrical magnet (N45 level, K ＆ J Magnetics), produce pin array magnetic Body combines the unit (Fig. 5 .).Pin magnet is inserted in 1/16 inch bore get out in 15x1x12 cm rectangle lucite piece. Also insert 4 bigger pins as block, with the commercially available 96- hole microwell plate of localization criteria so that each hole Center be aligned corresponding pin magnet end center.

Method.Through following modifications, carry out the test described in embodiment 14：All pipette steps are manually carried out, Put into 2 single 96 hole black microwell plates (Greiner, catalog number (Cat.No.) 675096).Magnetic is selected, in bar magnet group Attach together to put and magnetically select a flat board.Fixing other flat board on parallel bar magnet combination unit.

In another experiment, through following modifications, carry out similar test：Optiprep is not included in dye reagent Dense reagents..For this experiment, pin magnet combination device carries out magnetic selection.

Result.Figure 66 confirms the target signal section of the selection uniform deposition on imaging surface, and this allows to use Parallel bar magnet and bar magnet combination unit, calculate signal emission part using the imaging do not amplified.

Figure 77 shows the image from the test using pin magnet.The part selecting is heavy in imaging surface region Amass it is allowed to calculate signal emission part using the imaging do not amplified.Signal present in region around the string of deposits allows to comment Estimate unselected background.

Conclusion.Using several types and the structure of described magnetic combination unit, complete the particle magnetically responding Magnetic selects.Magnetic combination unit can be used in the different embodiments of the present invention, as selection power of the present invention.Mark It is specific that the magnetic of the target of note selects, and allows to calculate target by the imaging do not amplified, thus delicately detecting target Thing.

Alternate embodiment.In other embodiments of the present invention, it is possible to use the magnets of different compositions, and be this Known to field.

Described magnetic combination unit can be integrated into the subsystem of the embodiment of the present invention described in Figure 14.At some In embodiment, imaging container moves between magnetic combination unit.

Multiple magnetic combination unit can be incorporated in an analyzer for other embodiments.

Present embodiment describes several magnet structures, it is contemplated that other structures, and be known in the art, it There are different imaging hole geometry, and imaging subsystems used in the different embodiments of the present invention.

Parallel bar magnet combination unit (Fig. 4 .) allows to select with stationary arrangement simultaneously and be imaged, and this provides and is selecting step The ability of detection band is observed during rapid.This feature can be used for reducing test number (TN).

Embodiment 3. graphical analysis

General introduction.The Core Feature of the present invention is that, based on the imaging do not amplified of the analyte targetting, Treatment Analysis are tested. Present embodiment describes image analysis processing embodiment.

The feature of the image analysis algorithm describing in the present embodiment includes：Count individual signals part, when can not differentiate During single part, very large-scale signal performance measures accurate one count, in the large area meter of the object defocusing Realization on number, the realization on the wide scope experiment type based on test-specific analytical parameters, different types of fragment Exclusion, and detection error image (no illumination, image block, damaged shuttle, the shuttle lost).

Description.This image analysis algorithm provides full automatic analysis.There is provided input picture and with regard to producing image Experiment type information, analysis software generates numerical result, the number of signal emission part that its quantization exists in the picture. Image-taking system based on the test running and use is it is intended that image type.Described algorithm uses one group to be based on input picture The pre-configured analytical parameters of type.Using following step, carry out graphical analysis：Target area (ROI) calculates, framework divides Analysis, field flatten, shelter, the calculating of connected com ponents analysis, parameter extraction, classification and result.Following partly in describe each Individual algorithm process step.

Target area (ROI) calculates.The first step of graphical analysis is the calculating of target area (ROI).ROI is containing letter Number frame part (Fig. 2).For many experiment types, signal is comprised in circular hole, and described circular hole is in histogram frame In frame.The detection of ROI allows later analytical procedure only to process the pixel being found that signal wherein.

ROI detects by structural parameter control, described structural parameters are based on the experiment type inputing to algorithm.Real for some Test type, ROI does not change with image.In this case, using pre-configured ROI.

In the case that experiment type needs ROI detection, analysis uses edge detection algorithm, and this algorithm is used for detecting ROI And the difference of the background between the image-region outside ROI or peak-to-peak signal level.The use of background or peak-to-peak signal is also based on Experiment type.

In order to calculate ROI it is considered to be derived from one group of linear array of the pixel of image.Both horizontally and vertically selecting these Line.Every line forms one-dimensional signal.Run sequence filter on each line, to find background or peak-to-peak signal.Using having length The sequence filter of degree 20, background is found in 2 sequence, and signal peak is found in 18 sequence.Then, by the output of sequence filter Rising edge with length 80（In the case of predicting rising edge）With this reversing（In the case of predicting trailing edge）Related Connection.For every line, the new blank image of the pixel position corresponding with original line will be added in along association output.? Afterwards, for the shape mated with input hole, by two-dimentional associated application in this image.The maximum that ROI position correspond to correlator is defeated Go out.The program is also used for searching for different hole sizes.This process is three-dimensional search, and it searches the chi of the ROI with most relevance Very little, x position and y location.

Using last ROI be hole shape centered on the ROI position calculating.Based on input picture type, this shape Shape can be configured to different size, then measures ROI.In some cases, it is somewhat less.

Frame analysis.Pure frame analysis purpose be, it is determined whether labor should be skipped.This is real in the following cases Existing.

Signal level and region are too high for significant blob is analyzed.Because test has very high dynamic model Enclose, it may not differentiate single blob.In this case, analysis result is based on overall strength and area.Although in this situation Under can not possibly remove fragment, signal is so high so that overall result has good signal to noise ratio.

Frame analysis to check effective framework also by the presence finding mark.This includes the feature of the object of imaging, The edge in such as hole or reference mark.If feature does not occur as expected, reduce analysis, and report mistake.Inspection The condition looked into includes feature that is losing, fuzzy, non-suitable radiation and seriously defocusing.

Field flattening.Carry out the background level difference of correction chart picture using field flattening.It is used for compensating non-uniform lighting.If shone Bright system has defect, the LED such as crushing, and this can occur.When not knowing image condition before analysis, field flattens It is beneficial.This frequently occurs in scientific analysis application, and wherein experimental condition is change.The application of field flattening is to be based on to want The structural parameters of the experiment type of analysis.

When flattening using field, first pass through operation Ordination in all pixels of the part in ROI, estimation exists Background level in ROI.Pixel value at 10% is used as the estimate of image background.All pixels outside ROI are set For this value.

Then, divide the image into 10 x 10 square-section array.The part in each section is arranged as above Sequence is analyzed, to measure the background estimating value in this section.Measure the average of all sections background estimating value and standard deviation.If any Estimate exceeds more than 3 times of standard deviations than mean value, replaces it with this limit value.Similarly, if arbitrary value is lower than mean value 3 times of standard deviations, replace it with this lower limit.Limited estimate forms 10 x 10 pixel image, and each pixel correspond to Each limited background estimating value from corresponding section.

Optical low-pass filter is applied to the image from back.Then using interpolation, the image spreading obtaining is extremely former Beginning image size.Then deduct this background image from original image.Any pixel value less than 0 is set as 0.This forms field flattening The output image of process.

Shelter.Using the signal as separation detection for the image of flattening and the threshold value of background.This is realized with fixed threshold, institute State the type that fixed threshold is based on processed image.Following formation mask image：If pixel value is less than threshold value, will cover Covering pixel placement is 0, and otherwise, will shelter pixel placement is 1.

Connected com ponents analysis.Running connected com ponents analysis from sheltering of back.This produces a row image blob, wherein Each pixel in blob has 1 masking value, and is directly adjacent at least one of blob other pixel.In addition, from not 2 pixel not direct neighbors with blob.

In addition to blob list, to form image with original image identical size.Set every in this image as follows Individual pixel.If the masking value of this pixel is 0, it is set as 0.Otherwise, pixel value is set as the blob knot belonging to it The reference of structure.

Parameter extraction.Measure many parameters for each blob.These include center, according to pixels calculate area, Intensity (total pixel value), mean intensity, girth, minimum pixel value, max pixel value, width, highly, length-width ratio and tight ness rating.

Classification.It is then based on blob parameter, blob is divided into several classes.Described type includes signal, too small and cannot function as The blob of signal and different fragment type.

, there is one group of blob classifying rules in the image processing for every class.Every rule considered in the frame analysis stage The blob parameter recording and image width parameter.

By the change of shape, size, overall strength and intensity, fragment is classified.Rule is believed with image type and image Number total amount and change.If there is high RST, signal blob is more likely closer to each other, and looks like big blob.In this feelings Under condition, it is desirable to use bigger fragment-threshold, to guarantee that these big signal blobs are correctly marked.Classifying rules is based on figure As type.Common structure is using 3 groups of rules：One group is used for the low signal situation with tight fragment setting, and one group is used for There is the msp signal situation of average setting, one group is used for the high RST situation with loose debris setting.This kind of scheme will be believed Make an uproar ratio maximization, it limits the fragment of low signal, and wherein it has big percentage effect, and in the case of high RST suitably Count signal.

The calculating of result.The calculating of the number of the signal emission part existing in the picture is with always based on image type Signal level.The result count threshold for every class image configuration.If resultant signal level is less than or equal to this threshold value, this algorithm Result is set as be marked as the number of the blob of signal.Otherwise, result is set as：（It is marked as each group of signal The overall strength of mark）/ for image type construction signal emission part intensity.

Conclusion.This example demonstrates the imaging automatically calculating the number of signal emission part present in image divides The minimizing of the practice of analysis algorithm, described image is produced using the photodetector array not amplified.Present embodiment describes so Algorithm, it can separate signal and background, compensates luminous effect, ignores fragment, the image of detection mistake, and defeated in wide scope Enter and work on experiment type.

Alternate embodiment.The process step describing in the present embodiment provides the general summary of graphical analysis.It can Many such steps can be bypassed, and still produce useful result.Extra step can also be added.For example, it may be desirable to Pretreatment stage come to adjust in a particular detection system introduce distortion.

One replacement scheme of ROI detection is to search for one or more reference marks（If they are used for this purposes In）.

Another scheme of graphical analysis is simply to be accumulated in the value of all pixels of more than the threshold value of configuration.

Imaging tool such as Image Pro can also be used, manually carry out graphical analysis.User can manually set ROI and threshold value, and analyzed with being attached property of count tool.They can also select using this instrument to produce in count tool Blob list on region and strength range filter.Finally, user can manually indicate which blob is fragment, and should When being ignored.The overall strength of all signal blobs can be shown with instrument, and be recorded as result.

The analyzer that embodiment 4. does not simply automate

Present embodiment describes a very little analyzer, it is used for the sample with microslide size is held Device is imaged.But this analyzer provides strong cost-effective analysis for low processing capacity purposes.The analyzer of the present embodiment Provide following characteristics：Support multiple experiment types, adapt to microslide, be imaged from above to support top to select examination Test, adapt to the outside form such as lateral flow assay selecting of not needs.

Description.This analyzer is used for adapting to the sample on the microslide of standard or with similar type preparation.Figure 7 is the sketch of analyzer, and Fig. 8 shows photo.

Carry out lateral flow assay, wherein fixed bit on slide combination unit for the capture antibody anchorage using this system Put.Flow through with them, the target of mark is captured.Using the coated fluorescent grain of antibody, it is marked.

In order that using this system, user has prepared the captive test of 3 inches of 1 inch of X or less form, and puts test Hold thing to be placed on the platform that imaging occurs.

This system allows user's manually mobile input slide.User can also be using the thumb screw of mobile imaging table To control focus.

Described imaging subsystems are used for detecting fluorescence signal emitting portion (~ 475 nm excite/~ 535 nm transmittings).Close In the details of imaging, referring to embodiment 1.Imaging subsystems are by CCD camera (the Sony XCD SX- producing 8 gray level images 910) constitute.Carry out irradiance pattern picture using 2 Luxeon LXHL-PB09 blue leds (Lumiled LXHL-PB09).They produce The Lambertian radiation pattern of the maximum blot intensity of raw target.

By the Image Pro software application program from Media Cybernetics, Image Acquisition control is provided and divides Analysis.It runs on a personal computer, and described computer is connected on camera by IEEE 1394 (FireWire) interface. User starts image capture with Image Pro interface.Also using blob count tool, Image Pro carries out graphical analysis. Graphical analysis is as described in Example 3.

Conclusion.This example demonstrates one embodiment of the invention, it uses photodetector array, using luminous Diode carries out irradiation, the target imaging after selecting them by capture portion, to the single marking on microslide. This embodiment illustrates simple analysis instrument practice brief.

Alternate embodiment.Described analyzer can have the estrade of motorization, and it is moved left and right using worm drive (parallel to system forward position).This motor can be used for mobile estrade in image acquisition procedures, to allow to more than camera The regional imaging of framework.

Described analyzer can have relevant selecting module, and it selects magnetic force using top, will select power before imaging Put on test.

Described analyzer can reset into from bottom imaging, and selects magnetic module using relevant bottom, before imaging Selection power is put on test.

Embodiment 5. is used for detecting the simple analyzer not automated of multiple signal emission part

General introduction.Present embodiment describes the image-forming module that single sample manually operates, it is come using the imaging do not amplified 2 different fluorescence signal designation of emissions in detection single sample.This analyzer can be used for opponent's assemble in site and selection Multichannel test imaging, described test incorporates 2 unlike signal emitting portions with unlike signal feature（For example, 2 differences Fluorogen）Mark as them.It can be used for the imaging of other sample types, and described sample contains 2 different letters The mark of number feature, for example, detect the test of following cells：Wherein said cell with rubrum acid coloring agent pyridine as own in iodate inside Ground mark, and with the yellow-green fluorescence extra-granular that is attached on cell surface antigen mark.

Described analyzer accommodates reaction using commercially available or customized production sample bottle.Sample is prepared in off-line. This includes：Make mark part contact target with selected section, and the target of mark is deposited in detection band.After preparation, will The hole containing sample of imaging is manually placed in imaging fixing device.2 different excitation sources can be manually selected Irradiation sample is it is possible to manually change the launching filter being fixed on imager as needed.Connect by personal computer Mouthful, manually peration data obtains function, for controlling imaging function.

Description.The present embodiment is the particular of the image-forming module of analyzer, and it is suitable for 2 signal transmittings of detection Feature.Optical combination device is as shown in Figure 1.This embodiment be used for detecting fluorescein-sample fluorescing fractions (excitation peak 488nm, Emission peak 520nm) and Cy5 or Alexa 647 fluorescein (excitation peak 650nm, emission peak 668nm)

Sample in the hole with the clear and bright bottom detection surface of optics is manually placed on imaging fixing device (in figure Do not show) in.Imaging fixing device is by the holder of sample well（It makes hole be directed at suitable photograph machine testing by its design Position）Move along imaging axis with being used for making holder（To allow focusedimage）System composition.

Irradiation module is identical with module described in embodiment 1, and exception is, is not that 6 identicals LED are used for irradiation. It carries out irradiation using each wave-length coverage providing by replacing 2 different types of LED.In each wave-length coverage, equal Using 3 LED in the circular array of even distribution.In this embodiment, the LED for fluorescein spectral region is that Luxeon sends out Emitter 3W LED-Blue, Lumileds, LXHL-PB09, it produces the light in blue wave spectrum.Each LED with excite band logical Filter (20mmD, Chroma, Z475/49x) matches.LED for Cy5/Alexa 647 scope is Luxeon LXHL-PD09 is red.Each LED matches with exciting bandpass optical filter (Chroma HQ620/60x).

Described imaging system includes Mightex, Inc. BCE-BO13US camera（It passes through USB 2.0 and connects and individual People's computer docks）, for projecting image onto non-amplifying lens (Relay Lens, Edmund on CMOS imager Scientific, 45-760) and the launching filter that can manually exchange.For fluorescein spectral region, using Chroma HQ535/50m launching filter.For Cy5 scope, using low pass Chroma HQ665LP filter.

Operation.Operating personnel put into imaging fixing device ready sample.Filtered by installing suitable transmitting Device, and switch suitable LED set, select first signal transmitting boundary.Start the data acquisition of real-time mode, and pass through hand Building site adjusts detection the distance between surface and lens, focusedimage.Obtained in first spectral region by framework capture Image, adjust the time for exposure, thus unsaturated camera ground detection signal emitting portion.Filtered by installing suitable transmitting Device, and switch suitable LED set, select second signal transmitting boundary.Focus on dispensable, because it is at first Carry out under the irradiation of signal transmitting boundary.Image in second spectral region is obtained by framework capture, when adjusting exposure Between, thus detection signal emitting portion, and the capacity of unsaturated camera.In 2 signal emission part, photobleaching is had not In the case of sensitiveness, first signal emission part the most fast light is imaged so that manual focusing operation does not interfere with signal The sensitivity of detection.

Conclusion.This imager can be used for dichromatism detection.It can be used for detecting the single target of double labelling, or for many The examination of road is tested.This device can be regarded as obtaining the optical combination device of system for automated image.

Alternate embodiment.Can be for arbitrarily desired signal emission part to design light source and filter.By using The filter bar of motor-driven or wheel, can make launching filter exchange automation.Sample can be made as follows to imager Assume automation：By using robotics, including mobile example to obtain multiple images from single detection surface, and can be as Under make focusing operation automate：By the distance between software adjustment sample and camera and combined with graphical analysis, to examine Survey the best fit plane of focus.By being imaged to sample itself, or by reference mark present on the detection surface to sample well Imaging, can execute this operation.Or, can fixed-focus as follows：By design sample fixed system so that passing through automation Or when the placement of craft puts into sample in imager, sample is always in focal point.

Embodiment 6. Automatic analyzer software architecture

General introduction.The present embodiment details the software architecture embodiment for auto-control analyzer.

The present embodiment uses analyzer to control configuration processor, its script execution based on sign completely.Perform script is by shape The design of state machine controls, and the latter is using the analyzer state of very determination：Start（start）, guiding, initialization, start （kickoff）, suspend and terminate.

In addition, present embodiments providing the flexible architecture being extended by control script and extra-service. By order and state interface it is also possible to add multichannel user interface client.

Description.Fig. 9 shows the software block diagram of the present embodiment.Following partly in, describe the main of configuration processor System element, system service, data management and user and communication interface.

Configuration processor.The duration of runs that analyzer is responsible for by executor controls.The present embodiment uses and is write with Java Control configuration processor.The execution of the single control routine of this parts management, described control routine is system with commands sequence.Control Routine processed is write with Groovy script.This system is effective, because Groovy code can be compiled into Java when loading Syllabified code, and with configuration processor identical Java Virtual Machine in run.

The script manager of the configuration processor showing in fig .9 is responsible for loading and perform script.In order to support parallel control Activity processed, script should have one or more scripts and process, and each of which operates in single thread.By to system Service sends order, Script controlling analyzer.System service also provides for script and supports that function, such as Delay Service and script are processed Synchronize.In addition to close to system service, script can be close to different storage environments（memory contexts）, including Sample data, lot data and total data.

For Manage Scripts execution, configuration processor uses state machine architecture as shown in figure 41.In following paragraph In describe the operation of state machine.

Boot state is first state run upon actuation.Configuration processor runs boot script in this state.This holds Once initialization activity such as guides system motors so that motor controller position corresponds to physical location to row.When guiding pin At the end of this, configuration processor moves to init state.

Run initializtion script in init state.The general setting function of this execution, such as travel motor estrade arrives Their starting position.In addition, the realization of some diagnostic characteristics executes a series of diagnostic commands using initializtion script.Originally At the end of beginningization script, configuration processor moves to beginning state.

In beginning state, configuration processor reruns beginning script, and described beginning script checks entry condition.For example, Described beginning script can check input pickup and incubator queue, to observe whether input sample has been added in system, Or whether shuttle is ready to leave incubator.When finding suitable condition, start script and send signal to configuration processor, Configuration processor moves to running status.

Running status provides the disposal ability of circulation.It calls Run Script with fixed intervals, and described interval is to be based on to be System structure.In typical application, Run Script provides the control to main process task element.Configuration processor is maintained at running status, Until receiving time-out from order and state interface or ceasing and desisting order.After receiving pause command, configuration processor moves to temporarily Stop state.After receiving and ceasing and desisting order, it executes power-down sequence, and termination system.

Halted state is used for supporting diagnosis and software development.As shown in figure 41, when from order and state interface receive temporarily When stopping order, enter halted state from running status.When pausing, system is not reruned any script.But, by order and State interface can access system data.Furthermore it is possible to loading new script, or change existing script.Continue command with when receiving When, exit halted state.If there is needing activity sample to be processed, configuration processor moves to running status.Otherwise, it moves To init state.

In addition to current state, configuration processor uses sample manager to follow the tracks of the state of all samples in processes. Follow the tracks of the information on movable sample batch using batch manager.Each batch contains the experiment of all samples in this batch Type, process, expired and control information.By the batch identity of coding in sample bar code, by lot data and sample phase Association.

When the state of execution state, sample manager or record management server changes, configuration processor is by current state It is saved in nonvolatile storage.This information uses on startup, to rebuild current system after power-off or other system mistake Operation.

System service.There is the system service set corresponding with the main hardware elements in system.They provide simple Interface, script can control hardware using these interfaces.Extendible architecture makes introducing extra-service become to hold Easily.

Data management.Data management provides (Fig. 9) by sample manager and batch manager.For support structures and state User interface, by order and state communication interface, accesses these systems.

User and communication interface.As shown in figure 9, user interface client is communicated by order and state interface.Should Interface is supported to be connected with remote computer.This system can support multiple client.

Conclusion.This example demonstrates supporting the simplification of the practice of control system of automatic analyzer.It is expansible , flexible, sane, and support the quick exploitation of other analyser functions.

Alternate embodiment.Figure 76 shows the architecture of an extension, and it incorporates several user interface datas Management system.There is many users and system interface client.Come control system and report result using front panel.Printer carries The system having supplied another form exports.Transfer station is one or more client-side interface, and it allows input or scanning batch Card image.Transfer station also provides the mechanism for inputting or scanning usual identifier and relevant sample identifier.HIS / LIS interface is used for reporting result to usual information management system.Except the fortune being provided by sample manager and batch manager Beyond row time data management, there is data storage as shown in Figure 9 and analysis element.The sample that this element storage was processed Data and be scanned into the batch information in system.It receives sample result using order and state interface, and to batch Change in manager initialization and notice batch card data storehouse.User and external system interface can also access data storage And analysis element.The implementation options of this element includes relevant and flat file database.

The architecture of the present embodiment promotes the integration of service, to provide additional functionality.These can be included to new The support of system hardware element and the interpolation of new software service, the such as redundant interface with outer computer.

Architecture is also configured as easily supporting that user interface extends.This can include the support to new scanner and with The interactive voice response interface of voice recognition.

In addition to Groovy script, described system can run the script supported with any Java-JSR 223 The script of written.These include JavaScript, Ruby, Python and more than 20 kinds of other scripts.

In an alternative embodiment, there may be extra halted state, it runs and stops script, to provide termination The Flexible Control of sequence.

Embodiment 7. has the monocyte sample analyzer of the automation of integrated selecting module

General introduction.The monocyte sample analyzer of the automation describing in the present embodiment accepts shuttle, described shuttle It is proprietary cylinder, adapt to the test form using different specific target catching methods, and integrate for the target to capture The device of imaging.This embodiment can be ideally used to clinical sites inspection (point of care test).In addition, it is permissible For food production and veterinary purpose.

The present embodiment uses proprietary cylinder, one sample of single treatment.Described cylinder contains a series of operation single test or Reagent needed for parallel test, and it is automatically activated test when adding sample.

Described cylinder is inserted analyzer, and sample is added the sample well of cylinder.Then analyzer automatically carries out all need The test process step wanted, generates result, and this result is shown and prints.These steps include following function：Start reaction inspection Survey, test timing, magnetic selects, Image Acquisition, graphical analysis, and result report.In terms of the position of user, operation is very simple Single：Described cylinder is inserted analyzer, and introduces the sample into cylinder.All other operation is realized by analyzer.After off-test, User takes out cylinder, and processes it.

Described system is supported to realize multiple test array in single cylinder.

Description.The present embodiment is the embodiment using self-contained cylinder, and described cylinder automatically processes single sample every time.One Denier container is inserted in analyzer and sample is added in container, and analyzer just automatically carries out institute's test procedure in need, Generate result, this result is shown and prints.User reads result over the display, accepts printing from integrated printer Copy, and hospital information system can be sent the result to.

Needing low processing capacity in requisition in the case of check, this embodiment can be ideally used to clinical sites inspection. In addition, it can be used for food production and veterinary purpose.

Figure 10 shows an embodiment being intended for field test purposes.The analyzer of display every time with a cylinder Interact, for many purposes, this design based on the cylinder using.One sample can be used for running single examination in cylinder Test, or described cylinder can split sample it is possible to abreast run battery of tests.

Sample inputs.One new cylinder is put on analyzer by user first, as shown in Figure 10.Then, laboratory sample is added In cylinder, as shown in figure 11.By using the optical pickocff (OMRON, E3T-SR21R2M) of the change in detection particular bore, it is System detection has been added to the time of enough sample volumes, and is started to reaction timing (Figure 10) using this signal.Once detection To the presence of input sample, system waits for reaction and occurs in a reservoir.Stand-by period is based on the reality of coding in bar code The type tested.

Reagent treatment and other liquid.Because reagent is inside input pod, reagent and liquid handling occur in container Interior.Do not need other reagent.

Process container is moved.Container is manually added system, single treatment one, and manually take out from analyzer. Once in entrance analyzer, cylinder remains stationary in whole process cycle.In fig. 12, after test incubation terminates, analyzer Using linear actuators (Firgelli, L12-50-100-12-1) by magnet (NdFeB magnet 22x22x100mm, AllStar Magnets) move in cylinder location below, to select to reactant execution magnetic.The process that magnetic selects is such as Lower described.

Management sample input information.Design embodiment for a field test purposes, collect wherein in direct sequence Sample simultaneously adds in system.Process a test every time, each test uses a new cylinder.When each off-test, ought The result of front patient is printed upon on thermal printer (Seiko, DPU-30), and is shown in liquid crystal display (the LCD prison of Figure 13 Visual organ, AEI, ALCDP7WVGATS) on.Then user manually updates patient's record that write or electronics with new result.

With 1D each cylinder of bar shaped code labeling, the experiment type of described 1D barcode encoding container.This is by system processor Read using barcode reader (barcode scanner, Miniscan, MS1207FZY), as shown in figure 12.Based on scanning Experiment type, system processor (AMPRO, RB800) executes its analysis process.Described bar code also coded containers ID And lot number.

This embodiment allows to input patient information using front panel, or using hand-held bar code reader from test mark Symbol bar code directly scans.

This embodiment also supports the replacement scheme of sample patient association.The network interface by standard for this replacement scheme This embodiment and hospital information system (HIS) are directly integrated by (being connected by the IP of 10 or 100 baseT Ethernets).? In the case of being somebody's turn to do, user will usually test in identifier input embodiment, and this information is stored by system processor.

In order to ensure user has been properly entered test identifier, the Patient identifier in system queries HIS, and should Presentation of information is to user.User checks that this identifier is mated with patient.

When off-test and when information is fully inputted, system processor is communicated with usual hospital information system (HIS), Reporter assay result.

When new cylinder is inserted into analyzer, test id information in the past is eliminated, and can input the new knowledge of new test Other data.

Bar code information and experimental result and arbitrarily usually test ID is recorded in systems, user use front panel and Printer can be retrieved.

Select.This embodiment is selected using magnetic.This is implemented as described below：Using shown in solenoid, by magnetic group Attach together and put (NdFeB magnet 22x22x100mm, AllStar Magnets) and move in cylinder location below.System is then Wait magnetic selection time, it is based on test type.Once selecting to terminate, using solenoid, magnet is moved to their sky Not busy position.

Imaging.Once magnet is contracted, then start to be imaged.Image-forming block is as shown in figure 12.Imaging subsystems be designed to Fluorescent test mark works together, and described mark is activated by the blue light of 475 nano wave lengths, and launches the green glow of 535 nano wave lengths (embodiment 1).Light fixture, detection optics and camera are all located at below cylinder, and they here can be to the detection of cylinder Surface is imaged.

Described system uses 5,000,000 pixels CMOS (Camera, Mightex, BCN-B013) camera, and it generates 8 Monochrome image.

Gather 10 frame series, and add up, generate single 16 monochrome images and be used for analyzing.This process makes the survey of single image Amount dynamic range increases to 10 times.

Using 2 light emitting diodes (LED) producing blue wave spectrum light (Luxeon transmitter 3W LED- Blue, Lumileds, LXHL-PB09), realize illumination.Each LED with through 475 nano wave length light launching filter (filter- 20mmD, Chroma, Z475/49X) pairing.

In Fig. 10, imaging subsystems pass through one group of transparent window at input pod bottom, the presence of detection fluorescent material. Fluorescence signal passes through the launching filter being adjusted to 535 nano wave lengths.It is by non-amplifying lens (Relay Lens, Edmund Scientific, 45-760) focus on camera detector.

The present embodiment embodiment is designed to be used in single image to collect the data of up to 25 son test set, this Type depending on container.Differentiate individual signals emitting portion using cheap high-resolution camera.Using 25 son examinations Test array, have about 40 in the test of every height, 000 pixel.

Container is retained in the correct position in input slot, to guarantee adequate focusing.The container carrier of container and analyzer Total fabrication tolerance is less than ± 150 microns.This tolerance is in the depth of the focus of imaging system.In addition, container has one group of light Visible reference mark on.They are used for checking focus, correct container placement and confirming lacking of the fragment of interference Image Acquisition Lose.Without reference mark is detected as expected, then user is notified to restart to test with another container.

Result is reported.Result is reported on liquid crystal display and printer, as shown in Figure 13, and can also use With being directly connected to of hospital information system, automatically report.Referring to " management sample input information " part above.

Post processing.Once off-test and show result, user takes out cylinder.When former cylinder has been taken out, it is System gets out next test.

System controls.As shown in figure 12, the present embodiment embodiment is developed to using embedded computer to execute There are system control and process.This single circuit plate contain Intel Atom microprocessor and motor controller, display controller, 10/ 100 base T-network interfaces and other interface circuit needing.

Conclusion.This example demonstrates one embodiment of the invention, it is single that it to be located in reason automatically using cylinder design Sample, and report the array of up to 25 experimental results.Process of the test includes：Timed incubation in cylinder for the reactant, reacts battle array The magnetic of row selects, and using CMOS camera to capture result imaging, and the LED for irradiation.Using connection to the container Barcode scanner, result of the test is associated with patient information.Result is exported on display by analyzer, from integrated Printer printed copies, and send the result to hospital information system.

Alternate embodiment.The modification of this embodiment allows to add sample queue so that multiple cylinders can be processed, no Need further user input.This needs to add cylinder disposal ability, for cylinder being moved to the position on analyzer, and modification Cylinder-analyzer interface, to allow instrumentation to start the reaction on cylinder.

The Automatic analyzer of embodiment 8. energy high throughput analysis

General introduction.The format high throughput automation desktop analytical instrument describing in the present embodiment accepts microwell plate (96 Hes 384 pore structures) as shuttle, including relevant magnetic selecting module, for detection surface will be partially depositing in.It is whole Closed for being imaged the CCD camera of target, and have for focusing on, the customization software of graphical analysis and result report and hard Part.But the flexibility of this device and feature can provide strong cost-effective analysis for format high throughput purposes.This device is permissible For in drug screening and science, clinic, environment and quality of production laboratory.

Description.The test carrying out microwell plate outside analyzer prepares and assembles, using manual liquid handling step Suddenly.The definite step being related to depends on test to be carried out, but generally follows following codes.

Testing standard product are diluted to one group of certain concentration (test is dependent).By each normal concentration and laboratory sample 3 measurement aliquot pipettes in one group of stainless steel, one aliquot of each container.By isopyknic following substances One of add each aliquot, and be thoroughly mixed.There are 3 tests, they include to produce the reagent of positive test result (positive control), the reagent (negative control) of suppression test, buffer solution dilution (experimental result).

Then incubation at room temperature test mixture special time amount (test is dependent).While being incubated, will Dyestuff mat pipette is in the microtiter well for imaging.When the reaction is finished, by reactant mixture pipette to dyestuff mat Above.

Then microwell plate is placed on above magnetic catch combination unit, in room temperature deposition target 5 minutes.Work as magnetic At the end of capture, microwell plate insertion analyzer is imaged.Then analyze the image collection of generation, with determination test knot Really.

At the end of graphical analysis, take out microwell plate from analyzer, and put in biohazard waste canister.

Sample inputs.Analyzer is made up of flexible shuttle nest, and described shuttle nest accepts 96 holes or 384 holes knot The microwell plate (Figure 14) of structure.Analyzer accepts a microwell plate, but multiple tests are placed in single flat board. This allows, and analyzer analysis is any number of to measure reaction, until the capacity of flat board.

Reagent treatment and other liquid.Carry out liquid handling outside analyzer, including the assembling of test.Step is followed down State code.

Testing standard product are diluted to one group of certain concentration (test is dependent).By each normal concentration and laboratory sample 3 measurement aliquot pipettes in one group of stainless steel, one aliquot of each container.By isopyknic following substances One of add each aliquot, and be thoroughly mixed：The reagent (positive control) of positive test result will be produced, suppress test Reagent (negative control), buffer solution dilution (experimental result).

Then in incubation at room temperature test mixture 15 minutes.While being incubated, by the density mat pipette of dyeing To in the microtiter well for imaging.When the reaction is finished, by above reactant mixture pipette to dyestuff mat.

Then microwell plate is placed on above magnetic catch combination unit, in room temperature separate section 5 minutes.Work as magnetic At the end of capture, microwell plate insertion analyzer is imaged.Then analyze the image collection of generation, with determination test knot Really.

At the end of graphical analysis, take out microwell plate from analyzer, and put in biohazard waste canister.

Process container is moved.Realize the motion (Figure 14) of analyzer by the estrade of 2 motorizations.Using two dimensional dynamic Estrade (Prior H138A) motion of realizing in X (front and rear) and Y (left and right) axle, and carry out for localizing sample Imaging.Motion in Z axis (upper and lower) is realized by the estrade (Micos MT-40) of single motorization, and gathers for image Burnt.X-Y stage has 0.2 micron of resolution ratio on 2 axles.Z estrade has 0.5 micron of Motion Resolution rate.All motion hands Work is carried out, or the motion (only for X-Y stage) using premeasuring.

Management sample input information.Sample message, Test Information and position in a reservoir are by user record in experiment pen Remember in this.By with gathering the image collection name label figure in the container position of image and user input analyzer wherein Picture, analysis result is associated (Figure 52) with sample message.This describes in detail in following systems control division divides.

Select.Using neodymium (NdFeB) magnet, (22x22x100mm AllStar Magnets is referring to embodiment 2 magnetic Power), target analyte is selected by magnetic catch.Using relevant magnetic selecting module, the target of mark is deposited on detection table On face (Fig. 3).

Imaging.Imaging subsystems are used for detecting fluorescence signal emitting portion (~ 475 nm excite/~ 535 nm transmittings). With regard to the details of imaging, referring to embodiment 1.Imaging subsystems are by CCD camera (the Sony XCD producing 8 gray level images SX-910) constitute.Come irradiation imaging area using 4 Luxeon transmitter 3W blue led (Lumiled LXHL-PB09).Use Range sensor (Keyence LK-G37) carries out imaging focal length regulation.This system is by light fixture, detection optics and position Camera below container constitutes (Figure 14).

The image capture software using is with 2 model programs.Interaction observing pattern (also referred to as field mode) be used for from Camera captures continuous image stream.One of software interface programs button is when depressed, to preserve the list from this stream Individual image (Figure 50).

Program automatic image collection pattern so that the target hole containing test needs to focus on first.Then this program needs Hole site is imaged, this from the beginning of target hole (Figure 54).Once selecting to portal, software controls analyzer movement in Keyence Microwell plate above, wherein measures the distance in the hole of each selection.Be used focus on hole distance as reference, this program Calculate the focus correction factor in each hole to be imaged.Once finding all correction factors, move on cameras by face for this program Flat board, and after the Z axis adjusting each hole, to each borescopic imaging.This software programming is preserving each image is single literary composition Part, is used hole site, image collection title, current date and current time as filename (Figure 52).

Once having obtained image, by the customization automated software of our oneself exploitation, analysis of the image (embodiment 3).

Result is reported.This automated analysis software programming is that the result analyzing single image is shown in computer screen On curtain (Figure 74).This program is also used for the catalogue of analysis of the image, and result is exported excel table procedure or csv file (Figure 19).According to the position of collection image, report result.Then these image result are mapped to actual sample information.

System controls.Analyzer is built into, makes assembly be directly connected to PC, or connected by control panel.It is directly connected to Assembly on computer includes：The motor control panel (Galil DMC-2134) being connected by RS232 serial port, is passed through The range sensor (Keyence, LK-G37) that RS232 serial port connects, and (IEEE1394) is connected by firewire Connected CCD camera (Sony XCD SX-910).

The assembly being connected on motor control panel includes：The estrade (Prior H138A) of X and Y motorization, Z estrade Motor (Micos MT-40) and 4 Luxeon transmitter 3W LED- blueness (Lumileds, LXHL-PB09).

The control program customization software of grapho-analysis instrument in LabView (National Instruments).By device Manufacturer provides the device driver needed for control program.

After program starts, software is operated by guiding motor.By being moved rearwards by guiding motor, until it Reach beginning position or limit switch.In this point, motor position is set as starting point.To be programmed to it is allowed to by with Adjustment programme parameter in the interface of family, starting point is reset to arbitrfary point (Figure 53).After startup, program presents to 4 sheet formats of user Interface, as shown in Figure 50 53.

First table controls field mode operation.It is in office that it allows user manually to position the container in face on cameras Meaning point (Figure 50).This table is used for initial focusing, then starts automatic capture pattern and manual image capture.

In Figure 52, the 3rd table of display controls automatic capture pattern.Figure to be stored is inputted in uppermost textbox The catalogue of picture.The identification label of input picture set in following frame.Program construction is become, with this bookmark name+date and Time, md in the catalogue selecting.Also it is referred to as one of picture to be saved filename using image collection name Point.

Will ' Select Wells ' programs button is to start pop-up window, be graphically displayed microwell plate to be imaged, As shown in figure 54.On pop-up window, user selects hole to be imaged, and starts focal point control hole.Once selected aperture, user closes Pop-up window, starts automatic capture.Analyzer and then image capture executed as described above, and the prefix+hole position specified with user Put preservation file, filename adds date and time.

The 4th table that will be called ' Setup ' is designed to it is allowed to user is inclined by inputting X, Y and Z in motor pitch Move away from the starting point of change estrade.The number also allowing for user's change from the mobile required step in a hole site (claims in a program Make ' tile ') and used which flat type.

Conclusion.As described above, the multiple samples in microwell plate can automatically be analyzed by this desktop analytical instrument, to examine Survey the target complex compound of the single marking selecting deposition by magnetic.Combined using this imager comprising CCD camera and LED Device, the fluorescent material of deposition is automatically focused on, in the imaging of low magnifying power and analyzed, to produce result that can be quantitative.Should Analyzer can be used in format high throughput drug screening and science, clinic, environment and quality of production laboratory.

Alternate embodiment.There is the change that many can be used for this analyzer.Joint nest can accept different types of sample Product container, including 96- and 384- hole plate and microslide.

To change the wavelength that analysis analyte detection is used by using different filters and LED, alternate embodiment can With using different spectral regions.This allows to detect multiple analytes in single mensure.Retouch in detail with regard to what how this realized State, referring to embodiment 5.

Described device has loading magnetic selecting module, and it provides imaging, localizing sample container simultaneously, selects for magnetic (Fig. 4).Or, used in superincumbent embodiment, relevant magnetic station (Fig. 3) can be integrated in analyzer, as motorization Estrade can be to the station of its mobile example container.Other catching methods can be used for and above-mentioned similar analyzer Background in.

For image capture, substitute focus version and include, find the slope of the plane of container.This is implemented as described below：Using away from From 3 far points in container bottom for the sensor measurement.From these measurement results, the slope of Calculation Plane.With current focusing side Method is the same, and the method needs focus objects hole first, but the method corrects focal length using slope.This form is in practice Middle simplification, as shown in figure 53.

Embodiment 9. uses the Automatic analyzer of stage motion mechanism of robot input sample as needed

General introduction.In the present embodiment, shuttle (Figure 17) and Automatic analyzer (Figure 16) interact, to process Test and to the target in sample（If present）Imaging.Described analyzer comprises the CMOS photograph for being imaged to target Machine, and there is the customization software and hardware reported for shuttle transport, incubation, focusing, graphical analysis and result.Described point Analyzer has the treating capacity of up to 40 sample/hours, and can be used for high volume clinical laboratory inspection purposes.It can also For food preparation and veterinary inspector purposes.

Description.By the nose swab sample pipette of wash-out is entered sample well, prepare shuttle (Figure 17).Then close Cap, and insert analyzer input rank, as the single sample container for automatically processing.When shuttle is put into conveyer belt When in queue, sensor is freed.This issues analyzer signal, moving conveyor belt, and shuttle is on described conveyer belt simultaneously. Gantry robot's system, from conveyer belt mobile example container, is stood by each required for processing.Treating stations include bar code and read Take, grow start, fixed temperature incubate, measure reaction start, the reaction incubation in environment temperature, magnetic select and magnetically The imaging of the reaction selecting.Once analyzer terminates to analyze sample, result is shown on the lcd screen, prints on a printer, And LIS is sent to by network connection.Then automatically process shuttle in integrated biohazard waste shuttle. Following partly in be explained in detail in the process of shuttle.

Devise analyzer, and built with 2 queues, to accept the stacking (Figure 15 and 16) of shuttle.Design queue To accept the stacking of 1-8 shuttle.When heap is overlayed any one input rank opening, photoelectric sensor (Omron light Electric reflex reflection sensor E3T-SR21) it is triggered, send signal to control software, to activate stepping motor (Arcus DMAX- KDRV-23), stacking is moved in analyzer and processed.

When stacking is ready to process in any one queue, the uppermost sample that analyzer is processed in stacking first holds Device.There is above stacking photoelectric sensor (the Omron photoelectricity reflex reflection sensor E3T- being arranged on gantry robot SR21) (Figure 15).Each queue of sensor scan of described robot, is started with maximum stacks as high, and moves down, directly To shuttle trigger sensor.After finding, gantry robot takes off uppermost shuttle.

Shuttle movement in systems, completes (Figure 15 and 16) by 3 electric motor systems.These systems are referred to as input System, main platform system and imager platform system.Each system is as detailed below.Described system can independent operation, specific behaviour Need once in a while to synchronize.

Input system is by the single conveyer belt being provided power by above-mentioned stepping motor (Arcus DMAX-KDRV-23) (Figure 15 and 16) forms.Shuttle is moved to from initial entrance point and picks the position specified for gantry robot by described band. When shuttle above is in pickup location, the new shuttle of described Tape movement, until it contacts before it Shuttle.In this point, in shuttle slip underneath, described shuttle is queued up waiting pickup location band.

There are 3 stepping motors (Arcus DMAX-KDRV-17) (Figure 15) in platform system.Each motor It is connected to the straight line estrade (Automation Solutions, DL20DW-XZ) of different length.Estrade the longest controls stand Y (left and right) direction.This estrade is anchored on substrate.Y estrade platform connects the shortest estrade, the latter control stand X (front and Direction afterwards).X estrade platform is connected to control the estrade in stand Z (upper and lower) direction.Z estrade connects a pair of fork.These Fork has such part, and they allow to be directed at (Figure 17) with the part of molding in shuttle.Z estrade platform also connects Connect photoelectric sensor (Omron photoelectricity reflex reflection sensor E3T-SR21).Described sensor is used for measuring stacks as high, as above Described.

By adjusting X and Z estrade, stand picks up shuttle using fork.Once shuttle is caught by fork, X platform Son is moved rearwards by, with to Y estrade slot milling.In this position, Y estrade can move to shuttle at optional position Reason, and do not collide the structure of analyzer.

Imager platform system is made up of 2 stepping motors (Arcus DMAX-KDRV-17), and they are connected to 2 On straight line estrade (Automation Solutions, DL20DW-XZ).Long estrade is referred to as imager X estrade.This estrade controls The front and rear motion of imager stand.Imager X estrade connects imager Z estrade, and the latter controls the vertical fortune of imager stand Dynamic.Z estrade connecting platform, this platform has aligning parts on its surface, they and the similar aligned portions on shuttle Part overlaps (Figure 17).

Imager Z estrade is there is thin pitch screw mechanism with the difference of other estrades.It has 5 microns of resolution Rate, different from 50 micrometer resolution of the other estrades on analyzer.This difference allows fine focus regulation and the essence of height Thin control, to start reaction test.These part is described in detail below.

After input position picks up shuttle, it is brought to barcode reader (Microscan to main gantry robot MS1).In information including lot number, experiment type and experiment parameter for the 1D barcode encoding on shuttle.Work as reading When, information is stored in data structure control program, for following the trail of shuttle and retention analysis result.

Two classes are occurred to incubate in this analyzer.They are for the constant temperature incubation of sample grown with for measuring reaction Environment temperature incubates.After scanning shuttle bar code, sample initially enters growth hole.Main gantry robot is by shuttle Move to imager stand platform (Figure 15).After shuttle is placed on platform stand, it is flat that imager stand raises imaging Platform, the piston cap (Figure 17) on shuttle is oppressed by the part of imager Z tabletop.By depresses plunger, liquid Sample is forced to move to growth room from sample input holder（Growth agents are here by lyophilized）.Then, shuttle Put into the constant incubator (Figure 15) of loading by main gantry robot.Shuttle is incubated 4 hours at 35 DEG C, thin to allow Bacterium cell growth.

Described incubator have by custom machine manufacture part constitute shelf (upside, downside, front side, rear side, left side, Right side).Such part is contained at shelf bottom, and it coordinates (Figure 17) with the part on shuttle bottom.Built using insulating foams Culture tank wall, incubator is divided into 4 rooms by described insulating foams.The shape of the rear wall of incubator is suitable for 4 before 4 rooms The machine-made door of customization.Using actuator (Firgelli L12-50-100-12-I), open and close door.Incubator Heating uses fire-bar (OMEGA, SRFG-310/10-P), and they are from culture box top and bottom through outside.With insulation bubble Foam covers fire-bar and any outer surface exposing, except door.

After growth incubation terminates, start to test.Main gantry robot takes off shuttle from grown cultures case, and it is moved Move imager stand platform (Figure 15 and 16).After shuttle is placed on platform stand, by mobile platform until sample Piston cap (Figure 17) on product container is fully depressed by by the part of imager Z tabletop, and imager stand starts to test.Pass through Second depresses plunger, fluid sample is forced to move imaging chamber from growth room（Test reagent is here by lyophilized）.Liquid Body once enters imaging chamber, and reagent horse back is rehydrated, and starts to measure reaction.Imager stand returns pickup location, and main Shuttle is moved to reaction and incubates position by gantry robot.This incubation continues 15 minutes, and occurs in room temperature.

Described reaction incubator is made up of the system of 15 shelfs.Single shelf has part, described part with sample Part cooperation in container bottom, for positioning be aligned.

After reaction terminates, target is selected by magnetic.Shuttle is moved to magnetic from shelf by main gantry robot Body position (Fig. 3,15 and 16).Magnetic selects to carry out 5 minutes, and then shuttle is moved to imaging platform by main stand.As Shown in Figure 15, magnetic catch station is made up of 2 identical magnetic.Described combination unit contains rare earth solid-state version magnet (Nd-Fe-B N48 NdFeB, 22x22x100mm bar), as shown in Figure 3.This allows 2 shuttles in the overlapping time period Magnetic is occurred to select.

After magnetic selects, it is imaged.Imaging subsystems (Fig. 1 and 72) are designed to work together with fluorescence signal emitting portion Make.Signal emission part is excited by the blue light that the bandpass optical filter centered on 475 nano wave lengths filters.By with After optical filtering crossed by bandpass optical filter centered on 535 nano wave lengths, collect launching light.Radiation module, detection optics and photograph Camera is all located at (Figure 15) below the shuttle of imaging suite device.Described imaging subsystems are detailed further in embodiment 1 State.

After magnetic catch terminates, shuttle is moved to imager gantry robot from magnet station by main gantry robot (Figure 15).Shuttle is moved to distant place sensor (Keyence LK-G37) by imager gantry robot.Measure and each The distance of imaging hole, and calculate focal length.Imager gantry robot is positioned on CMOS camera (Mightex BCN-B013) Face, the latter obtains 8 gray level images in each hole.To each borescopic imaging 10 times, and add up, entered with obtaining more high-order gray level image Row analysis.

Carry out graphical analysis using the customization internal algorithm described in embodiment 3.After analysis terminates, imager gantry robot Shuttle is moved to ejection system.Described shuttle is then departed from platform, and enters biohazard waste canister (figure 16).After analyze data, result and cylinder information are stored on computers, print (Seiko, DPU-30), and show Show upper (Figure 16) in LCD touch screen monitor (AEI, ALCDP7WVGATS).

Described system is designed to by the platelet computer (Ampro, RB800R) of single operation Ubuntu Linux 2.6 Control.All component connects to computer directly or through control panel.The assembly being connected directly to computer includes motor Controller (Galil, DMC-2183-DC24-DIN), LCD monitor (AEI, ALCDP7WVGATS), CMOS camera (Mightex, BCN-B013), range sensor (Keyence LK-G37) and printer (Seiko, DPU-30).By electricity The assembly that motivation controller connects includes the stepping of photoelectric sensor (Omron, E3T-SL22), main stand and imager stand Motor (Arcus, DMAX-KDRV-17), the stepping motor (Arcus DMAX-KDRV-23) of input table carrier, and LED (Lumileds, LXHL-PB09).

With desktop test contrast.Operation test in described analyzer, and the examination with the craft preparation running on estrade Test and compare.Code is as follows.In 32.5 DEG C of growth medium TSB (soy broth that trypsin treatment is crossed, Acumedia Catalog number (Cat.No.) 7164A) in culture staphylococcus aureus (ATCC bacterial strain 29213) culture 2 hours, to reach logarithmic growth Phase (OD₆₀₀= 0.3).Count staphylococcus aureus thin in the Petroff-Hausser counter on Zeiss microscope Born of the same parents, and in fresh TSB, cell is diluted to 0,700,2100 and 8400 cell/35 L solution, for testing.According to 1: 2000, mixed with the 0.9% sodium chloride reaction containing the green I of 100 L SYBR (Invitrogen, catalog number (Cat.No.) S-7563) for the dilution Compound, by pipette, is sufficiently mixed the anti-staphylococcus aureus protein A magnetic-particle of 25 L 0.005 % w/v chicken (strictly according to the facts Apply and produce described in example 1, carry out following modifications：Using the anti-albumin A of chicken (Meridian OEM catalog number (Cat.No.) C5B01-296) antibody （It is in 10 mM phosphate, 140 mM sodium chloride, 3 mM potassium chloride (Calbiochem catalog number (Cat.No.) 524650), 0.05% w/ V polysorbas20 (Acros catalog number (Cat.No.) 2333600010), 2 mg/mL bovine serum albumin(BSA) (Sigma-Aldrich catalog number (Cat.No.)s A3059), in 0.05% w/v ProClin 300 (Supleco catalog number (Cat.No.) 48912-U) pH 7.4）, and 125 L are in institute State the staphylococcus aureus dilution in TSB, and incubate 15 minutes in the dark in environment temperature.After incubation, by reaction mixing Thing is divided into 6 equal portions, and 35 L reactant mixtures are covered in pre- decile in 96- hole half area diameter clear and bright bottom blackboard 65 L dyestuffs-mat solution in 3 holes of (Grainer, catalog number (Cat.No.) 675096) and in 3 imaging holes of described device 15% v/v OptiPrep (Sigma catalog number (Cat.No.) D1556) and 2 mg/mL Chromotrope 2R (Sigma-Aldrich C3143 on).Selected by magnetic, cell-Particle complexes are deposited on the bottom in all holes.The hole of 96 orifice plates is placed on magnetic Excellent upper 4 minute.Described bar magnet is using the structure of 22 x, 22 x 100 mm permanent magnet described in fig. 20.Then take from magnet Go out flat board, and be placed in format high throughput automation imaging analysis instrument (embodiment 8 and Figure 14).0.1 second open-assembly time, in analysis To borescopic imaging on instrument.Then using above-mentioned software, calculate single fluorecyte.The hole of device is put in α analyzer, the latter is certainly Dynamic moving cylinder selects station to magnetic, then arrives imaging station.Then 0.1 second open-assembly time to borescopic imaging.Using imaging software (embodiment 3), calculates single fluorecyte.

Result.Fig. 6 A shows that aloft reason amount automates the golden yellow grape running on imaging analysis instrument and α analyzer The contrast that the fluorescence of coccus test counts.Result is similarly in experimental error.Fig. 6 B shows the single dyeing do not amplified The digital picture of aureus cell and the contrast with the sample not having cell.As a result, it was confirmed that on analyzer and Similar result is produced by the reagent in the imaging hole of the device of Manual analysis.

Conclusion.This analyzer can automatically process shuttle, have minimum user and interact.Described sample holds Device is interacted with analyzer, and it supports that process as needed, sample grown, the imaging do not amplified and integrated waste are processed. It allows to have been integrated into signal transmitting to be analyzed and selected section using the CMOS camera of standard in the detection of low magnifying power On single target.

Change.One variant of analyzer includes high power capacity grown cultures case.Such big incubator allows analyzer every Hour processes at least 40 shuttles.Due to its little contact area, it can make preferable format high throughput machine be used for clinic Laboratory, food preparation and veterinary inspector purposes.

Embodiment 10. uses the Automatic analyzer of fixing band drive motion mechanism input sample as needed

The Automatic analyzer describing in the present embodiment accepts shuttle, selects using the magnetic on shuttle Capture target, and combine the photodetector array for no amplifying target imaging.Described Vessel Design makes user's liquid input sample Product reagent specific with experiment type separates.This embodiment makes all needed for each input pod produces experimental result Step full automation, and support the multiple experiment types based on Container Type and batch code.

The present embodiment supports sample input as needed, wherein using gravity cover queue.This ability allows user to exist Add input pod, the up to capacity of queue of 8 containers to analyzer when they are ready to.

Embedded processor control system data analytic function.When user input is to off-test, used container exists Dispose in integrated biohazard waste canister, sample advances and process is full automatic.

This embodiment can be used for medium volume (12/ hour) clinical laboratory inspection purposes.It can be used for eating Thing is processed and veterinary inspector purposes.

Method.User, closes the lid from hospital's collection device pipette sample to container, sealing container input sample hole, And by usual bar code applications in container.User and then put into container in the stacking with other containers, or by single sample Queue (Figure 20 and 21) put into by product container.Analyzer processes each container according to following order.

Process container is moved.On band with teeth, by the container gravity cover put in input rank stacking to analyzer. When container is placed on band, (Omron photoelectricity can poly- reflective sensor E3T- to be arranged on the fluorescence detector with top layer SL22) detected.Sensor activation system control software, it is led with stepping motor (Arcus DMAX-KDRV-17) movement Lead device band with teeth.This band draws bottom container to barcode scanner (microscan, MS1 FIS-0001- 000XG), to read the bar code of connection.From bar code, system determines batch information and container validity.Band and container are set Count into and there is coupling aligning parts, thus system control can be passed through with the mobile container of the continuous sequence of specific timing incubate, Imaging and biohazard waste position (Figure 21).

Management input sample information.Proceed to on-test with container, barcode scanner (barcode scanner, Microscan, MS1 FIS-0001-000XG) read the bar code connecting, to determine batch information and container validity.

Reagent treatment and other liquid.After reading bar code, container proceeds to subsystem, and it starts the test in container. Actuator (Firgelli L12-50-100-12-I) engages the screw-cap (Figure 21) on container, and passes through screw, right Sample well applies pressure, to promote fluid sample to enter the room equipped with dried reagent.Liquid in sample rehydrated positioned at sample Reagent in container, and start to measure reaction.

Incubate.Before user loads container, carry out sample grown incubation.The incubation of test depends on conveyer Timed motion.Conveyer is set to, before reaching selection estrade, with optimal for reaction incubation assays type Speed accurately moves container.

Select.Above Tape movement experiment container to magnet combination device, there is the selection of target.Parallel magnets The choosing of the target that (NdFeB magnet 22x22x100mm, AllStar Magnets are referring to embodiment 2 magnetic force) is marked Select.The time that magnetic selects depends on Tape movement speed.Described speed depends on experiment type.

It is explained in detail in system control, imaging, result report, process container motion and management sample defeated in embodiment 9 Enter information.

Conclusion.This example demonstrates the one of device is designed, described device has sample treatment as needed, makes No enlarged drawing array image-forming with Magnetic Isolation method and specific target.

Alternate embodiment.For the test needing growth, described structure can include high-temperature control incubator, and it will Stacking queue continuously given by the container incubating.Using the dual colour imaging described in embodiment 5, extra part can be imaged. By the magnet additional image of embodiment 2, overall size can be reduced.

Embodiment 11. has the automation continuous sample vessel analysis instrument of screw-drive mechanism

The Automatic analyzer describing in the present embodiment accepts airtight shuttle, adapts to using magnetic methods specificity The test form of ground capture portion, and it is integrated with the device for the imaging of no amplifier section.

The present embodiment supports sample input as needed.This ability allows user to add to analyzer when they are ready to Plus input sample.

The embodiment 10 being functionally similar to above of this embodiment, but highlight alternate embodiment at following aspects Application：

Method.Analyzer docks (Figure 22 and 23) with the shuttle containing loaded reagent and stream control part.In sample After collection, the shuttle (in the stacking of most 8) sealing is placed on from the nearest input (Figure 22) of input slideway user Position.Shuttle in input slideway advances through analysis as detailed below treatment element.After analysis terminates, container deposits Biohazard waste canister (Figure 22) internally.

Sample inputs.This analyzer accepts single or stacking container (Figure 22 and 23) as needed.Manually to cunning Road moves container, and they enter analyzer downwardly against gravity in slideway, and wait in line on-test.Bar code is in this position Read by subsystem, as described in detail in embodiment 10.

Reagent treatment and other liquid.While container enters in slideway, the initialization (Figure 22) reacting.One Container part is pulled out stacking by individual single leadscrew.On actuator (Firgelli L12-50-100-12-I) Stopper head moves down, and promotes the matching block on container, and forces fluid sample to enter the room containing reagent.Plunger retraction, Leadscrew replaces container to enter stacking, and it waits here is engaged by main boot screw (5 microns of pitch, custom design). When main motion screw initialized container mobile to magnet, all containers and then simply one queue position in whereabouts.

Incubate.Before inserting container in queue, carry out sample grown incubation.After reaction starts, container is retained in vertical It is allowed to the process time needing in straight queue.In bottom, the mobile container of leadscrew of active force passes through the residue of analyzer Part.

Process container is moved.Elevator landing uses actuator (Firgelli L12-50-100.12-1) to slide from input Road mobile example container (Figure 23).The leadscrew of motorization and the mobile container (Figure 23) of the platform promoting.

Post processing.After imaging, container is moved to integrated waste canister (Figure 22) by worm drive.

Conclusion.As embodiment 10, this example demonstrates the sample input as needed of shuttle.It connects By shuttle, adapt to select power specifically to capture the test form of target using magnetic, and be integrated with for becoming to target The no magnifying optics of picture and photodetector array.

Alternate embodiment.After adding polychrome imaging sub-component, it is possible to authenticate go out multiple experiment targets, as embodiment 5 institute State.Internally before analysis estrade, grown cultures case can be added, to allow sample grown.In addition, mobile band input can be replaced For slideway, as described in Example 9 so that being automatic to the advance of input rank.

Embodiment 12. contains the automation continuous sample cylinder analyzer that single plane transports transmission mechanism

General introduction.The Automatic analyzer describing in the present embodiment uses subsystem, and it is in separation, shuttle The image detection do not amplified, as described in Example 10.This embodiment makes needed for each input pod generates experimental result The automation of all steps, and support user input monocyte sample.The present embodiment is supported continuously to locate in the speed based on experiment type Reason container.One test needs to be processed for 15 minutes, and treating capacity is 4/hour.

As embodiment 10, embedded processor controls data analytic function to execute automation by system.From User input is disposed in integrated biohazard waste canister to used container, and sample advances and process is full automation 's.

This embodiment can be used for low volume (4/hour are loaded using single container) clinical laboratory inspection and uses On the way.It can be used for food preparation and veterinary inspector.

Description.User accepts sample, and described sample has been collected and has been enclosed in sample together with loaded reagent and stream control part In product container.User is placed on input area (Figure 24) container.Container advances through analysis as detailed below treatment element.Analysis After end, container is deposited in Internal biological harm container.

Sample inputs.By being placed on each on the carrier of particular design, container is directly inputted container and processes kinetic system System.Described carrier has coupling tolerance and the mechanical registeration part with shuttle, places and user's positioning for simple.

When a new container is placed in empty carrier, by fluorescence detector, (Omron photoelectricity can poly- reflective sensor for it E3T-SL22) detect.This sensor activation system control software, this software activates stepping motor (Arcus DMAX- KDRV-17 stepping motor), drive rope with mobile.Drive rope to draw the carrier being dynamically connected to above flat surface, so that container is advanced and wear Cross process sequence.System control by rope and carrier with specific timing, the mobile container of sequential order pass through incubate, imaging and Waste position.

Reagent treatment and other liquid.After reading bar code, container proceeds to the subsystem (Figure 24) of mobile liquid.Activate Device (Firgelli L12-50-100-12-I) is fixed on above beginning target mark, when container is to start target mark Correct position when, another optical pickocff (Omron photoelectricity can poly- reflective sensor E3T-SL22) perceives.Work as sensing When the system of device alarm correct position controls, the plunger part on container depressed by actuator.Fluid sample movement is entered to contain by plunger There is the imaging hole of dried reagent.The rehydrated reagent of fluid sample, starts to measure reaction.Actuator and then contraction, container is ready to Process further.

Transfer system.Container is by using the stepping motor (Arcus DMAX-KDRV-17 stepping motor) being connected with rope It is moved through system.There is also 2 class transfer systems.First, using buffering guiderod, cylinder is transferred to imager.This separate imaging Assembly, and reduce system vibration effect.Linear actuators (Firgelli L12-50-100-12-I) is independent of driving mechanism Ground is mobile, keeps main system timing determination.Cylinder is moved litter-bin (Figure 24) from imager by linear actuators.

Management input sample information.When container moves to on-test (Figure 24) from input, barcode reader (bar shaped Code scanner, Microscan, MS1 FIS-0001-000XG) scan bar code when container passes through it.Bar code is used for Determine that batch information and container validity manage input sample information referring to embodiment 10.

Incubate.Before user loads container, carry out sample grown incubation.The incubation of test depends on delivery system Timed motion.Conveyer is set to, before reaching selection estrade, with optimal for reaction incubation assays type Speed accurately moves container.

Select.It is moved to above magnet combination device with experiment container, the selection of target occurs.Parallel magnets are (real Apply example 2 magnetic force) selection of target that is marked.The time that magnetic selects depends on Tape movement speed.Adjust this speed to reality Test the needs of type.

Explain imaging and result report is processed in embodiment 9.After imaging terminates, container is deposited on integrated biological danger In evil litter-bin (Figure 24).Empty carrier returns to user input position now.

Conclusion.The present embodiment highlights the low processing capacity analyzer with simple motion and transfer system.It executes sample Sample target in container selects the crucial processing function with the image detection do not amplified.

Alternate embodiment.With queuing replacement directly input that (such as in embodiment 11) can realize as needed defeated Enter model.Combination selects and imaging is as staying station altogether, such as in example 2, can provide the benefit of double treating capacity.Finally, make Used in the dual colour imaging described in embodiment 5, extra target can be imaged.

Embodiment 13. shockwave system software architecture

General introduction.The present embodiment details the software architecture embodiment that can be used for auto-control analyzer.

In addition to directly controlling analyzer, this embodiment provides for special needs in surge test is applied Part.These include and the order of situation order concentrated and control interface and patient management network application program.

The present embodiment controls configuration processor using the analyzer based on customizing script instrument, and described instrument is from extendible Execution object model set up by markup language (XML) script.

This embodiment is stored using linked database and managing patient and experimental result data.

Description.Execute this system, the compatible operating system of Microsoft Windows is run.It is by a group window Process forms, and they are communicated with customized information collection by transmission control protocol/Internet Protocol (TCP/IP) interface.Using standard Database interface, wherein need database to login.This design allows system to be used in multiple computers, for very big rule Mould is applied.

The software architecture of the present embodiment is as shown in figure 25.Configuration processor, system clothes are provided in following paragraph The general introduction of the main software function of business, data management and user and communication interface.

Configuration processor.Analyzer control element provides the perform function of the execution of auto-control analyzer.It includes Interface and the TCP/ with one group of service process with the interface, graphical analysis and relevant Database Systems of analyzer console IP interface.

Configuration processor has controlled the analyzer of processing line effect, and wherein reactant moves through station, and processes generation At each station.This system is occurred in previous cycle using the strategy based on circulation, the wherein all process activities on all stations In.This system then moves to next circulation, and with new system mode repetitive cycling process step.It is presented herein below and can follow The high-level embodiment of the simplification of process type occurring during ring.It should be pointed out that following the tracks of the process of each test；Only exist When movement test needs, just operated.

Abreast execute following：

Carousel and station are processed

By advance carousel, circulation starts.This moves each and is reacted to next process estrade.

Then, abreast treating stations sequence

Reagent stations:Mobile reagent robot inputs to reagent, is picked suitable with the correct passage containing liquid processing system Work as reagent, mobile reagent robot, to suitable mixing cup set, deposits reagent

Mat station:Mobile mat pipette, in mat holder, aspirates mat, moves to empty imaging cup, distribution pad Son.

Transfer station:If this is even numbered rounds, mobile transfer robot, to the mixing cup completing, picks from 2 cups Reaction liquid, and take out pipette.If being odd numbered rounds, move to imaging cup, deposit liquid is in 2 cups, and raises Pipette.

Sample station:Every 6 circulations, take sample from new input test tube, and for 6 tests.If necessary to new sample Product, mobile example pipette is in sample tube, and aspirates the liquid of enough 6 samples.Then, in each cycle, mobile Sample pipette is in mixing cup, and distributes sample, then raises sample pipette.

Sample cleanup station:This system is designed to there is 2 groups of sample pipettes.When one group in use when, another group In cleaning.If this is first of 6 cleaning circulations, mobile untapped sample pipette cleans mould to sample pipette Block, starts to clean.If this is last cleaning circulation, stops cleaning, and mobile example pipette is to ready position.

Hybrid station:Mobile mixing transducer, to contact mixing cup, runs transducer, retraction transducer

Imaging station:Mobile image instrument combines the unit with contact imaging cup, opens illumination, obtains image, closes illumination, Retraction imager combines the unit, analysis of the image, and exports analysis result to database.

Cup cleaning:Mobile cup cleaning combination unit, in cup, starts cup cleaning stream control part, waits, stop Only cup cleaning stream control part, retraction cup cleaning combination unit.

Shake reagent in bulk, to guarantee uniformity.

Input sample is processed:If this is last of 6 circulation sample sequences, mobile input rank is to next Individual sample.If current input rack terminates, project this support, and load next support.

By the flexible script set with customizing XML schema definition, drive configuration processor.The program defines 3 class nodes：Knot Structure, mechanism and execution.When system starts, script is compiled into object model, and wherein each object correspond in XML script One execution node.These object tissue become task list, and described list is the ordered list of executing successively of task.By same Step ground calls execution method on each object successively, is executed.

In addition, node execution can also abreast occur.This obtains the support of the thread using each parallel task list.

Simple embodiment shows described above, and the operation of needs depends on circulation and system mode.By using script The representation language of object model is supporting it.

Representation language supports that the compound of standard calculates and logical operation, and it can access and following relevant storage rings Border:

System.This includes previous cycle numbering.This to be increased by each circulation of the execution before executing in script.Pin This node can be used numbering cycle and modulo operator as the condition controlling multi cycle activity.

Current test by node processing

Current system circulates

Present node

Each executable node can have the structure being defined as text-string and/or condition expression.This is starting When compiling, and execute node when run.

In arbitrary storage background, structure representation can be set as 0 or bigger variable.

Only when condition is expressed and returned actual value (non-zero), execute node.

When processing script it may be necessary to synchronize the activity of parallel point attachments present treatment.For example, enter when reagent pipette is mobile When entering and leave pipette position, reagent in bulk should stop shaking, or before taking current sample, input sample test tube should not Work as movement.Process synchronization in order to complete script, this embodiment uses the script node type of one group of specialization, its support sets Put, clean and wait the condition specified to be formed.In this way, a script processes and can wait another, to impose a condition.

System service.There is the system service corresponding with each main hardware elements in system.These are shown in figure In 25.Each service to execute as single Windows process.They use the TCP/IP interface with customized information collection, with With executive communication.This architecture simplifies software maintenance, and promotes the interpolation of New function.The application of TCP/IP allows Service runs on a single computer.

Data management.Data administration subsystem provides patient's tracking, remote task arrangement and automatic data analysis. It has following characteristics：

Database stores all relevant samples and system information, including analysis result, system architecture and software version.

Integrated barcode reader follows the tracks of sample.

Software can identify control, and automatically sets up calibration curve.

Network interface provides local or long-range data input data analysis.

Order ＆ control interface provides remote management, task arrangement and safeguards.

User and communication interface.This embodiment supports several users and communication interface, including following.

Analyzer console.Analyzer console display system state and result summary information.It is used for supporting that system is tied Structure, diagnosis, maintenance and operation.

Console to execute as independent operating system process, and it is using TCP/IP and the execution with customized information collection Interprogram communication.This interface to be set up as client/server model, wherein analyzer control server can support one or More analyzer console clients.This solution provides integrated console to show（It operates in identical with configuration processor Computer on）With the console running on the remote computer.

Order and control interface.Order and control interface provide the connection controlling with external circumstances, described external circumstances Control is the management of the overall response to the emergency relevant with surge test.Order and control interface use above-mentioned TCP/ IP console interface to communicate with analyzer control.It can also access data management system by the database interface of standard.

Patient management network application program.Patient management network application program is used for collecting and managing patient information.This leads to It is usually used in inputting patient's contact and historical information, as a part for sample collection process.This application program and data management system System communication, but do not need to dock with configuration processor.

Data analysis web application.Data analysis web application provides different reports, and described report is total Tie total data result.This application program is communicated with data management system, but does not need to dock with configuration processor.

Laboratory information system/hospital information system interfaces (LIS/HIS) interface.LIS/HIS interface provides and marks The contact of accurate health care system.It is used for for experimental result being reported directly to usual data management system.

Conclusion.This example demonstrates the simplification of the practice of control system, described control system support automatically analysis Instrument, and surge test workflow can be managed.It is extendible, flexible, sane, and supports other analyser functions The quick exploitation of property.

Alternate embodiment.A replacement scheme using condition expression on each node is that have process expression Specialization node.This includes condition node, its evaluation expression, and only calls its child node（If expression is true 's）.It also includes " set " node, and it can be write as variable under the background of storage.

The architecture of the present embodiment promotes service assembly, to provide additional functionality.These can include：Support new System hardware element, add new software service, the such as redundant interface with outer computer.

Described architecture is also configured as easily supporting that user interface extends.This can include, and supports new scanner And with voice recognition interact voice response interface.

Embodiment 14. has the Automatic analyzer for format high throughput surge test of loading liquid process.

General introduction.Automation quasi shock waves analysis instrument is designed to, the single test group run in large sample series is provided Format high throughput Automated inspection.It is designed to adapt in biodefense or public health emergency（Wherein thousands may It is exposed to single pathogen or other factors）In inspection needs.This kind of scheme needs very high in peak capacity Treating capacity and simple analyzer are installed and are operated, section for a long time.

Analyzer is self-contained, portable and extensive, because operating environment can change, from hospital emergency room to building temporarily Vertical field hospital.Described device can be outdoor for field, parking lot or High School Gymnasium etc..

Automation surge test analyzer accepts sample container queue, processed with it, records each sample.Analysis Instrument combination unit test reaction in a continuous manner, wherein by a series of agent transfer of sample and loading in mixing cup, incubates Then experiment reactant is transferred into being imaged in ware by experiment reactant.Imaging ware containing experiment reactant is retained on magnet Face, to apply selection power to reactant, deposits signal in detection band, then not amplifying with CCD camera Acquisition Detection band Digital picture.Load Images analysis meeting provides the reading of the target level in each sample.

Needs to format high throughput, cost-effective, hypersensitization the test of molecular targets, create low to platform The needs that waste produces.Make the volume minimization of solid expendable waste, the volume of waste stream of biohazard can be reduced and disappear The totle drilling cost of the person of expense.By reusing and reusing including mixing cup (also referred to as reaction cup) and imaging cup and suction nozzle Assembly, it is possible to reduce rubbish.These assemblies are cleaned thoroughly between samples, to guarantee the low Residual contamination of sample and reagent And cross pollution.By reducing sample contact, such as using contactless mixing and the distribution of contactless reagent, also make waste stream minimum Change.Because these assemblies are from not in contact with sample, they can infinitely be reused it is not necessary to cleaning or changing.Also select surface Process and material, so that sample and reagent Residual contamination minimize.For example, it is coated the suction nozzle of customized production with Teflon (Cadence Science), and syringe bushing pipe is polytetrafluoroethylene (PTFE) (PTFE) pipe, it has the minimum friction system of any plastics One of number.The internal liquid of reagent in bulk is processed and is used for low-down experimentation cost.

Baby, the elderly or other product can be included for making reagent consumption minimum, increase patient throughput and patient The situation of the people of raw low sample, low sample volume is important.The needs to preparation of samples are also made to minimize or eliminate this needs Small sample volume collection a large amount of patients wherein are needed in the potential unordered and chaotic environment of quick screening be Beneficial.

Analyzer managing patient information in a secured manner, and provide in hospital database system, central command and diagnosis Person and reagent in bulk resupply between radio communication.Safeguard and demand for services is minimized to routine work, wherein device is short Just can operate in set-up time, and can continuously run several days.

Description.Device is to accept with processing line system similar mode and to process sample (Figure 48).Sealed stepping follows Ring carousel is processed with certain order mobile example, and one of or more sample handling procedure occur in each disk Belt position.Carousel movement system (Figure 45) has 100 recipients (Figure 31) to mixing cup and imaging cup.Circle Disk conveyer belt uses stepping motor (Oriental Motor Co., DG130R-ASAA) advance one when each circulation starts Individual position.Subsystem accesses one or more cups (Figure 33) in each cycle.System uses 6 second circulation time.

Cup counterclockwise rotates one step in each cycle, wherein in particular procedure order of steps determination sample.First First, diluent is deposited in mixing cup reagent subsystem.Then, sample removal sample is held by pipettor (Figure 49) metering ground Device, and put into mixing cup.Add the final reagent including signal transmitting and selected section, and mix this combination.Mat is distributed Enter and be imaged cup, and incubate the sample mixing together with reagent 5 minutes.The sample of reaction is carefully transferred to imaging from mixing cup Cup, makes it keep swimming in above mat.1 minute magnetic selects to deposit on the bottom by random magnetism selected section, so Here it is imaged afterwards.After off-test, cup will be mixed and imaging cup will thoroughly clean, and prepare to reuse.Waste liquid is sent To the biohazard loading with holding vessel.

Sample inputs.First step of determination sample includes：User collects sample, is inserted on device, device Automatically perceive, and measure sample in reaction cup.User collects sample in shuttle, as shown in figure 31.Sample is held Device is added to support（In the set of most 6）On, as shown in figure 32.Support is put into gravity cover queuing system (figure 44).Most 16 supports or 96 shuttles are queued up simultaneously in a device.

Gravity cover queuing system includes several function sub-components.Photoelectric sensor (Omron, E3T-FT12) detection is new The position of other supports in the interpolation of support, and monitoring queue.Support is by bilateral drive belt (Stock Drive Products, A6B3-D188025) drive and advance, described bilateral drive belt has by stepping motor（It has closed loop and amplifies Device (Oriental Motor Co., AS46AA)）With then linear dual actuator (Firgelli, L12-50-100-12-1) The timing belt wheel (Stock Drive Products, A6A3-12NF03706) driving.Barcode reader holds from sample Device scans sample message, and transfers the information to the computer loading, and follows the tracks of for test.

Support is added in gravity cover queue, as shown in figure 44.By support is placed in vertical alignment next Above individual, add support.If there is no support, then support is moved to nethermost position.This system is supported to be placed on water The stat process of the support on the right side of flat queue.These supports are always processed before the support of vertical alignment.

Details is moved in input rank.Shuttle input rank is mobile to be occurred in a series of steps.First, optical sensing Device detects support, and falls it with dual actuator.With tooth with process in support bottom on part engage, and band is to moving to left Dynamic, until first actuator is cleared.When support during optical pickocff mensure is processed leaves first actuator.Queue In the support that is lowered by of other supports keep.First actuator and then rising, to accommodate the next support in queue, and Tape movement, the support in processing leaves second actuator.Second actuator and then rising, to accommodate support above Queue.Support in process is moved to the left, until first shuttle is alignd with sample input position.Using optical pickocff To measure the support in process and to be contained in the exact position of shuttle therein.

The shuttle being later with system is ready to, Tape movement, until next shuttle is in sample input Position.After all samples container in processing support, the support in process moves in shuttle biohazard waste. Next support repeats this process, and the support until loading is processed.

Last assembly of sample input subsystem includes a pair of rotary sample pipette.Figure 58 explains this system Top view, wherein 2 sample pipettors are close to shuttle.In the structure shown here, a pipette is cleaned in cleaning (Figure 49), another measures sample in reaction cup simultaneously.After the distribution of each sample, pipette switching task is so that just The pipette of the allocated sample is cleaned, and the pipette just having cleaned processes next sample.

Each sample is carried out with 6 tests.Following experiment details an example.Sample pipette aspirates simultaneously and is used for The sample volume of all 6 tests.In each cycle, sample pipette distributes 10 microlitres of samples to current input mixing cup In.After 6 sub-distribution, the next sample tube in input rack moves to the position described in the mobile details of input rank above Put, and be processed in a similar manner.

Liquid handling.Many liquid handling functions are existed on system.These include inputting pipette, reagent pipette, mat suction Amount and sample transfer pipette, cup cleaning and mixing.Figure 64 shows liquid handling assembly sketch.The assembly of liquid processing system Including sample, the single syringe pump of mat and transfer station (being Tecan unit number 20738291 here), 2 be used for passing Send many-syringe pump (XMP 6008 8- passage numeral syringe pump, Tecan, 20737367), the rotation of all 12 kinds of reagent Rotary valve (XLP 3-port, Tecan, 20738291), the PTFE pipe of passive check valve, reagent and carrier fluid (Upchurch Scientific) and Tygon formula R-3603 pipe（For other pipes such as cleaning and waste）.It is included in Other pumps in this analyzer include 8 Mini-Wash membrane pumps (MiniWash full panel, Tecan, 20739017)（For being cleaned with clean water and washing）With 10 membrane pumps (KNF Neuberger, NF5RPDC B-4), it With for cleaning and biohazard purification NaOH, bleaching agent, detergent certain concentration compatible.

Use injector system for each pipette station.Each injector system is combined with kinematic system, wherein first will Pipette moves to source container.Then pipette is moved in purpose container by pumping liquid, distributes liquid wherein.Use Syringe pump (listed above) is moving the liquid at each pipette station, and each syringe pump has integrated valve, and it is permissible Select one of 3 positions.

The operation of valve allows one of 3 pumping actions.The pipeline between pump and suction nozzle is opened in one position, and this allows pumping With distribution liquid or bubble.The pipeline between pump and system fluid is opened in another position, and this allows following startup pump：From system Fluid aspirates, and distributes to the suction nozzle above cleaning.This setting is also used for terminating suction and distributes, and moves pump simultaneously. For example, this allows the single passage in set pipettor to control, and described set pipettor moves all channel pump simultaneously.3rd The pipeline between system fluid and suction nozzle is opened in individual position.This is provided for cleaning pipettor and starts pipeline.Syringe pump System fluid side has the option also being driven by valve system by membrane pump.This is used for starting pipeline and cleaning suction nozzle.

Pipette cleaning is important for making Residual contamination and minimizing cross-contamination.It is carried out as follows pipette clear Clean：First suction nozzle is moved to cleaning, here, system liquid is rinsed through it.Membrane pump discharges fixing device waste liquid, And give the adjoint waste storage container of loading., with transfer station using a pump being additionally connected with cleaning, it is with being for sample System fluid rinses suction nozzle outside, with the outside of thorough washing suction nozzle and inner side.

Include several liquid treatment plant in analyzer.Figure 49 shows from above 2 sample pipette combination units Sample pipette.These combination units include suction nozzle, the pipe of syringe pump system, electric rotating motivation, vertical electric machine, sample Pipette cleaning and the mixing cup accepting sample aliquot.

Described system uses a sample pipettor, and shuttle from process for the sample in processing is moved to 6 Mixing cup, as described in Sample input above divides.While a pipettor shifts sample, other washed.For every Individual fresh sample, their handoff functionalities.Work is in each cycle, to aspirate the enough volumes of each sample first, then distribute Enter in new mixing cup.

The reagent pipette unit using is as shown in figure 45.12- channel system is transferred to liquid from reagent container (Figure 55) Mixing cup.It by vertically and horizontally motor estrade mobile (Figure 58), and liquid by more than 2-syringe pump mobile (referring to above Details).In each cycle, each reagent passage can be assigned in the mixing cup of channel position.In each cycle, soft Part controls syringe pump valve so that the reagent only needing pumps out from reagent container, and is assigned in mixing cup.

Mat allocation unit is the additional channels (Figure 45) on agent combination device.This system uses dyestuff mat, its Before selecting step, it is placed on below reactant.Selection can be drawn the target being chosen with signal emission part mark and be passed through pad Son.This can reduce imaging background, and this to be realized beyond the visual field of imaging system by keeping free signal emission part.Should Mat allocation unit is driven by syringe pump, and mat reagent is allocated into being imaged in cup by each cycle.

Another pipetting systems is used for transferring the sample into the mat (Figure 46) of imaging cup after reaction incubates.Sample moves Liquid straw combination unit is made up of 2 suction nozzles, the pipe of syringe pump system, rotation and vertical electric machine.Sample transfer is double following Ring operates.In first circulation, the liquid carrying out 2 neighbouring mixing cups of comfortable transferring position is aspirated by 2 transfer pipettes. Then, liquid is dispensed on above the mat of 2 imaging cups.In second circulation, transfer pipette is cleaned.

After reaction, selection and imaging, off-test, cup needs to clean, and is that fresh sample is prepared.The cup cleaning using Stand as shown in figure 47., to be cleaned across the order of 7 estrades, each circulates one for each mixing cup and imaging cup.There are 6 clearly Clean estrade and 1 are dried estrade.When each estrade starts, cup cleaning unit is lowered into 7 pairs of cups.Then, membrane pump Engagement, to distribute and to aspirate cleaning solution.Finally, this pump unclamps, and cleaning unit raises in end-of-cycle.Cup cleaning combination unit (Figure 47) it is made up of 6 pairs of cleaning units and 1 pair of drying unit.Each cleaning or drying unit are once used for a cup.Cleaning Unit is made up of 2 concentric tubes, and its middle external tube distributes cleaning solution, and inner tube is aspirated.Final cleaning estrade is that aspirator is dried, its It is made up of single aspirator pipe.

In some cases, liquid reagent needs to be thoroughly mixed, to meet experimental performance requirement.Described system uses 3 Ultrasonic surface sound wave (SAW) mixed cell (Advalitix), as shown in figure 56.Add with sample, mix.In circulation During, mixed cell raises the liquid memory contact mixing cup so that it.There is integrated amplifier (Oriental Motor, AS46A) closed loop stepping motor be connected on vertical linearity axle (Deltron, DL26L-70-ST-C-PH), To move blending apparatus.After contact liq holder, transducer is engaged, and reduces with mixed cell, closes closed loop end End.

When analyzer enters run-up mode, by including the Xiamen of electronic security(ELSEC) interlocking mechanism or visiting, user is permissible Close to bulk liquids and waste canister.

Incubate.After being sufficiently mixed reactant as mentioned above, start to incubate.Incubative time is 5 minutes, and this is based on 6 seconds Circulation time.Reaction transfer pipettor terminates incubating, and selects with after-applied magnetic.

Management sample input information.The management design of input sample information becomes to work in surge test purposes.Due to Surge test frequently occurs under emergency situation, and this system is designed to full automation.This makes the complexity of user Littleization, and reduce error chance.

This system provides network interface using the webserver, for capturing patient information.This allows simultaneously using perhaps Many patients input station.At each patient's input station, take sample, and be stored in barcode sample container.Give to patient Identification (ID) unit (such as wrist strap, Figure 68), it is matched or corresponding with the ID of shuttle.Id information and patient information one Rise in scanning or input patient's record.As described above, by sample tube addition system.

When sample treatment starts, read sample bar code.Sample bar code is stored as a part for sample record. At the end of processing, calculate final analysis result, and be stored in sample record.This information is passed through sample ID and is recorded with patient Associated, described sample ID is recorded in sample collection process.This system followed the tracks of using relevant database patient and Sample data.

Select.The specific selection of target is the important step of test process.This analyzer selects to capture using magnetic Magnetic selected section, described magnetic selected section is provided of the chance with reference to target that may be present in sample.When imaging cup When moving to above magnet, magnetic is occurred to select, as shown in figure 57.Selection time is 1 minute, and includes in described capture time Period（Sample liquids are captured）Dispersion space motion on magnet.This system is using described specific in example 2 Bar magnet structure.

Imaging.This system is using imaging system described in embodiment 1.It uses CCD photodetector array (2M picture Plain CCD camera, uEye, UI-2550-M) executing the imaging do not amplified to large sample target region.

Combined the unit by mobile cameras in each cycle, realize focus adjustment, as shown in figure 57.To have integrated The closed loop stepping motor (Oriental Motor, AS46A) of amplifier be connected to vertical linearity axle (Deltron, DL26L-70-ST-C-PH on), with mobile imaging system, make it lift imaging cup and leave the fixing distance of optics.Cup It is less than the depth of field of optical system with the mechanical tolerance of image-generating unit.As described in Example 3, calculate graphical analysis.Figure 63 shows Image from type testing capture.

Result is reported.Using network interface, result is reported to multiple client.This interface is supported different reports and is divided Analysis inquiry.Result is additionally shown on system control position.In addition, this system is designed to, by order and control interface, by result It is sent to provisional orders system.

System controls.System control hardware include component computer, motion controller (8- axle step-by-step controller Ethernet, Galil, DMC-2183-DC24-DIN) and include the stream control Component Control System (Cavro, PN 740029) of intelligent I O board. Stream control Component Control System contains stream control component controls plate, and it is docked with component computer by RS 485 universal serial bus.All Syringe pump and Cavro smart valve are controlled by this plate.Membrane pump is controlled by intelligent I O board.

Surge test software is as described in Example 11.Software timing arrangement includes the high level running in each cycle Process.Follow the tracks of the process of each test so that only just executing operation in the case of movement test needs.Many effects are parallel Ground execution, is processed including carousel and station.

One circulation is from the beginning of carousel advances.This each reactant mobile processes estrade to next.At other Reason station series-parallel ground occurs.Reagent robot moves to reagent input, picks up suitable reagent here.Then, reagent machine Device people moves to mixing cup, deposits reagent here.Mat pipette moves in mat holder, aspirates mat, moves to Empty imaging cup, then distributes mat.During even numbered rounds, sample delivery station robot moves and enters the mixing cup completing, from 2 Reaction liquid picked up by individual cup.During odd numbered rounds, transfer robot is mobile to be extremely imaged cup, liquid deposition in 2 cups In.Every 6 circulations, sample robot is from new shuttle aspirated specimens, and is allocated in 6 neighbouring mixing cups, for 6 Individual long run test.Sample pipettor moves shuttle, and aspirates 60 μ L.Then, in each cycle, sample pipettor moves Move into mixing cup, and distribute 10 μ L sample, then raise sample pipettor.Sample cleanup station is designed with two groups of samples inhale Buret.While a pipette sample, another is cleaned.For front 6 cleaning circulations, untapped sample pipettor moves Move into sample pipette cleaning module, clean at this moment and start.In last cleaning circulation, cleaning stops, and pipettor moves Move ready position.Mixing transducer moves fluid contact mixing cup, and transducer runs, and then retracts after mixing terminates. Imaging station combination unit is mobile to open LED to contact imaging cup, obtains image, closes LED, imaging suite device is retracted, analysis Image, by analysis result information to database.By cup cleaning combination unit is moved in cup, there is cup cleaning Operation, starts cup cleaning stream control part, clean run 4 seconds, stops cup cleaning stream control part, then stops cup cleaning group Attach together and put.Each circulation shakes reagent in bulk once, to guarantee uniformity, and prevents from precipitating.In 6 circulation sample sequences A period afterwards, input sample processes the next shuttle moving to input rank.When all samples container in support When all processed, support is launched into biohazard waste canister, and the next support in queue advances, as mentioned above.

Experiment.On surge test analyzer, the Bacillus anthracis in people's whole blood is detected by automated analysis (Anthrax) lethal factor.

It is thin in people's whole blood for measuring that this experiment describes full automatic format high throughput surge test analyzer Verticillium toxin（Bacillus anthracis lethal factor）Application.This mensure uses mouse monoclonal anti-Anthrax lethal factor-bag Signal emission part and selected section are attached to contained in human plasma sample by the particle of the fluorescence and magnetic of quilt On lethal factor molecule.Selected using magnetic, by dyestuff mat, fluorescent grain-lethal factor-magnetic-particle complex compound is sunk Amass in detection band.Sample carrier is presented to analyzer, described sample carrier contains the lethal factor having filled variable concentrations Whole blood sample.Reactant in assembly analysis instrument, and incubation reaction hole, then covers each reactant in imaging hole Above the mat of dyeing, and magnetic selection platform is transported in hole, automatically to borescopic imaging.

Method.All load reagents are entered in the reagent cup of prototype format high throughput surge test analyzer.In computer Under control, by full automatic robot pipettor, carry out following all pipette steps.First, by 10 L 200 MM EPPS (Sigma-Aldrich catalog number (Cat.No.) E9502) buffer solution（It contains 400 mM 1,3 diaminopropanes (Sigma- Aldrich catalog number (Cat.No.) D230807) pH 7.8）Add in reaction cup, then pipette 10 L reagent（Containing 1 in PBS Mg/mL alginic acid (Sigma-Aldrich catalog number (Cat.No.) A2158), 2.5 % w/v polyvinylpyrrolidone (Sigma- Aldrich catalog number (Cat.No.) PVP40), 0.5 mg/mL ox gamma Globulin (Lampire Laboratories catalog number (Cat.No.) 7400805) and 1 mg/mL mouse gamma globulin (Jackson Immunoresearch catalog number (Cat.No.) 015-000-002)）.Plus Enter 10 L and fill anthrax lethal (people's whole blood of (List Laboratories, catalog number (Cat.No.) 172b).Subsequently, 10 are added (fluorescent grain (anthrax LF- FP) of anti-hTSH antibody labeling is following to be prepared L anti-Anthrax lethal factor fluorescent grain： Using standard method (Bioconjugate Techniques, Herrmanson Academic Press, 1996), using two Step carbodiimide and N- sulfo group HOSu NHS reaction, used in mouse monoclonal anti-Anthrax LF (IQ Corp., Catalog number (Cat.No.) LF-IQ) free amine group on antibody connects 500 nm fluorescent grain (Invitrogen catalogues of carboxylated chemically Numbers 8813) 0.007 % w/v dilution) and 10 L anti-Anthrax lethal factor magnetic-particle (using with fluorescence above Prepared by particle identical method, through following modifications：Described antibody is mouse monoclonal antibody) 0.05 % w/v dilution, By load（onboard）Blender mixes, and incubates 6 min.During incubating, automatically add in single imaging cup Enter mat reagent (30% Optiprep (60% w/v solution of the Iodixanol) (Sigma-Aldrich of 90 L dyeing D1556) 10 mg/ml Chromotrope 2R).After incubation, 40 L reactant mixtures are layered on the dyestuff-pad in analyzer imaging hole Above sublayer.Then imaging cup is automatically moved to above the magnet in analyzer, and carry out Magnetic Isolation 1 min.Will After magnetic-particle deposits in detection band, imaging cup is automatically moved on imaging table, is then imaged on analyzer, expose The light time is 0.1 second.Then calculate single fluorescent grain, and using the software on analyzer, analyze sample in an automated manner Product result.

Result.The data producing using full automatic surge test analyzer is shown in Figure 74.This figure shows Show the dose response curve produced by image obtaining using software automation analysis.These results confirm to use do not have The imaging do not amplified of any washing step is to from complex matrices（As human blood）Bacillus anthracis lethal factor complete Full-automatic, specific and sensitive detection.Figure 63 shows the image from type testing capture.

Conclusion.This example demonstrates a device embodiment, one of or more shuttles can be straight Accept in the device for format high throughput surge test.Described device is integrated with customization magnet array（For applying Selection power）And CCD camera（For the imaging do not amplified）.The repetition profit of the liquid handling of reagent in bulk and suction nozzle and cup With the low cost of each test can be provided, and so that the accumulation of solid waste is minimized simultaneously.

Change.There are many potential changes, those listed in describing in detail including superincumbent device.Circulation time is permissible It is adjusted to more or less than 6 seconds, to adapt to the parameter needed for special test.Described device can using disposable cup or Suction nozzle, this can aid in makes Residual contamination and minimizing cross-contamination.Described device can include more or less of reagent Pipette, each of which can be close to one or more reagent.The replacement that display in Figure 59 can be used is dried suction nozzle design, Or can be using using capillary replacement sample collection running stores (Figure 60).Sample input can be substituted with combination unit Sample pipettor, described combination unit deposits the sample directly from shuttle, such as shown in Figure 61.

Embodiment 15. is used for the analyzer based on cylinder of the automation of format high throughput surge test

General introduction.Present embodiment describes a kind of analyzer, it provides the Automated inspection with ultra high throughput.Will This system is designed to for biodefense or public health emergency, and it needs to check and thousands of may be exposed to pathogen Or the people of other factors.Analyzer accepts single sample test cylinder.Each includes the lancing for aspirating capillary blood sample Pin.Capillary blood is directly collected into cylinder from patient.Described cylinder includes carrying out the one group 6 required all reagent of test.This is real The scheme of applying makes to produce all step full automations needed for experimental result from each input cylinder.

Description.Figure 28 is the side view of the surge test system based on cylinder.Portable analyzer has wheel, is used for Quick arrangement and installation in urgent surge test situation.Close with user function is on the side of analyzer, including Load shuttle input, LCD reads and controls, close to waste and front console and storage.

Sample inputs.Using the lancet for aspirating capillary blood loading, sample is directly collected into test cylinder (Figure 26), and by wound packages it is loaded into, in portable cylinder carrier (Figure 27), being used for being conveyed to instrument.It is filled with them, carrier quilt It is loaded in the dead slot at instrument tip.Figure 29 explains the design of analyzer.

Process.The activated bath of reaction carousel dropped into one by one by cylinder from loading support, starts anti-here on cylinder Should.After carousel progressively rotates in the counterclockwise direction so that incubating at 6 minutes, cylinder passes through magnetic selecting device, shares 1 Minute.Then it step into imaging station, here by transparent detection surface, reactant is imaged.Explaining in fig. 30 makes Timing with cylinder rotation.Finally, container launches the waste canister (Figure 29) into loading, under loading in carousel One cylinder replaces it in identical position.Litter-bin can be contained in the used cylinder consume in a day.

Described analyzer uses the element of other embodiments.Embodiment 1 provides the description of imaging subsystems.5000000 pixels CMOS camera shoots the image of observation window.This captures all 6 reacting holes in the picture.Final image is by 10 picture frames Summation formed.This can make Dynamic Range increase to 10 times.Proprietary software analysis in the computer loading is final Image, as described in Example 3.Focusing is based on fixing camera and container position.Total machine and container tolerance are less than focus Depth.

Input sample information is run identically with those described in embodiment 14 with the management that result is reported.

System controls:All analyzer operations（Including timing and scheduling, error handle and recovery, data storage Deposit, data transfer, system diagnostics and graphical analysis）All by the computer controls of little loading.The computer loading also controls subsystem System assembly（Including motor control panel, reaction carousel, load carousel, LED controls, camera-enabled and aobvious Show plate）Operation.Systems soft ware is as described in Example 13.

Conclusion.This example demonstrates the high throughput analysis system based on cylinder, its adaptation is used magnetic force as specificity The test form of the selection power of ground capture target, and the nothing being integrated with for target zooms into the photodetector array of picture.By it It is designed for shock wave purposes, it needs portability and easy installation（Replace when being used for local gymnasium or auditorium etc. Subrogate when putting）.It is using the system not needing liquid handling or outside offer liquid reagent.

Alternate embodiment.It is also envisioned that many other sample loading patterns are substituting tube stent Load System.In reality Apply the complete replacement surge test system design describing the liquid handling device substituting cartridge system in example 14.

Embodiment 16. be used for format high throughput surge test have liquid handling moveable format high throughput automatic Change analyzer

General introduction.Movably automation surge test analyzer is devices which, it accepts containing fluid sample The queue of shuttle, executes several process steps to each sample in series, then selection power is put on test, be used in combination The image that photodetector array capture is not amplified.Device provides the automation inspection of the ultra high throughput with single experiment type Test.

Described system is by the format high throughput architecture of the system described in embodiment 14（There is liquid handling）With The mobility of the system described in embodiment 15 and design of transportation are combined.Format high throughput is by reagent in bulk（Each test Low cost）Internal liquid process provide；Reagent bag can not be added in halt system ground.Liquid handling, reaction carousel (Figure 35) allow to test 3 samples with other sub-portfolio devices simultaneously.Extensive and be designed to be installed into and stackable there is wheel System in the storage container of son, can promote storage, transport and install (Figure 70).Thus, moveable high throughput analysis instrument Can be used for biodefense or public health emergency, it needs to check thousands of pathogen or diseases of may being exposed to People, and wherein need quickly to increase the ability tested in given place, i.e. when outburst occurs on a town or ground Qu Shi, mounted spendable analyzer pedestal may be not enough to dispose the unexpected shock wave of test demand；In the present embodiment Described in analyzer be moveable, and there is format high throughput, so new analyzer moves to locality as needed.Separately Outward, described analyzer is designed to, and under the crisis situations that can not obtain the personnel with previous experience, can rapidly be transported Defeated, install and use.

Description.Analyzer in Figure 69 is format high throughput, moveable, the surge test system based on container Front view.Figure 70 shows unit in container and how stacked containers.Movably analyzer is moveable, has wheel Son, arranges and installation for quick in urgent surge test situation.Close with user function is in this side：Main reagent holds The loading of device, LCD read and control, close to waste and front console and storage.

Analyzer system operation is based on loading carousel and reaction carousel (Figure 29).Described process is The continuous productive process line model discussing in embodiment 14.

Sample inputs.User collects sample to proprietary container from patient.Include the lancet for blood collection (Figure 26).Sample from a patient is loaded into a container by user.In this embodiment, lyophilized reagent is located at room In, described room is covered by the clear and bright non-blooming observation window of optics, to allow to be imaged.By one or more appearances containing sample Device is loaded into support, and described support is seen above Figure 29.This support whereabouts entrance empty position (when each circulation starts, Carousel 1 backing positions of advance).Analyzer top input carousel moves, in the counterclockwise direction until sample Container reaches starting position.If it is empty, shuttle is placed in the reaction disk transmission of activated positions a container Band.

Process container is moved.Figure 30 is process model.In activated positions, the actuator (Firgelli of fixation below L12-50-100-12-I) align with container so that the plunger in container applies pressure to fluid sample.This pressure will force liquid Body sample enters reaction zone, and it is mixed with reagent here.This starts the stage of reaction.Carousel is counterclockwise from activated positions Rotation, reserves a position, falls from input carousel for next container.In the reaction, separate and select and signal Emitting portion is closed with target materialization.In rotation, incubation reaction thing 6 minutes.Then it enters magnetic force area, here, selects Power can make target target and the sample of reaction separate.This selection is 1 minute.After magnetic selects, container is imaged, analysis, and shows Show result.Finally, container is launched the hazardous waste (Figure 29) into loading, next input pod is (from top disc transmission Band) replace it in same position.Litter-bin can store the treating capacity of 1 day.

Described analyzer uses the element of other embodiments.Embodiment 1 provides the description of imaging subsystems.5000000 pixels CMOS camera shoots the image of observation window.This captures all 6 reacting holes in the picture.Final image is by 10 picture frames Summation formed.This can make Dynamic Range increase to 10 times.Proprietary software analysis in the computer loading is final Image, as described in Example 3.Focusing is based on fixing camera and container position.Total machine and container tolerance are less than focus Depth.

Input sample information is run identically with those described in embodiment 14 with the management that result is reported.

Prepare for next sample.After ejecting container, reaction carousel is ready to accept a new sample Container.This new container falls into the room reaction carousel from loading carousel.

System controls:All analyzer operations all by the computer controls of little loading, are pacified including timing and sequential Row, error handle and recovery, data storage, data transfer, system diagnostics and graphical analysis.The computer loading also controls subsystem The operation of system assembly, including motor control panel, reaction carousel, loads carousel, LED control, camera work( Energy and display board.Systems soft ware is as described in Example 13.

Conclusion.Present embodiment shows that adapting to magnetic force be used as the test shape of the selection power specifically capturing target The exploitation of the system of formula.The nothing that it is integrated with for target zooms into photodetector array and LED irradiation and the Load Images of picture Analysis.It provides ultra high throughput and waste containment.It can be used for shock wave purposes, and by using having the liquid of loading The portability to increase analyzer for the container that body is processed, and do not need outside liquid.

Alternate embodiment.By executing directly inputting of single container, will support that expanding to single test runs.Make With dual colour imaging, other targets can be imaged, as described in Example 5.Using single serpentine band（Rather than single load and Reaction carousel）To reduce height and the weight of second carousel.

Embodiment 17. has the automation high throughput analysis instrument of a large amount of loading tests.

General introduction.Automatic analyzer described in the present embodiment is devices which, it accepts shuttle, and has There are the many tests to multiple targets using loaded reagent.In embodiment described in the present embodiment, analyzer has Loaded reagent, to realize the test to 100 kinds of different analytes.Analyzer automatically processes each sample, applies selection power, and Using low magnifying power large area imaging, with the target of photodetector array detection mark.Accept ability, the use of the sample of wide scope Loaded reagent quickly executes the test of wide scope, can provide the low cost of each test, and provide the user test using software Information so that this analyzer is highly suitable for needing the situation of very format high throughput, such as in clinical labororatory.

This analyzer makes user's cost minimization, and this is realized by making the solid waste of biohazard produce minimum, This is particular importance for high volume user.Include mixing cup and reaction cup by recycling and reuse and suction nozzle exists Interior assembly, reduces solid waste.These assemblies are designed to through material and surface treatment, thus have minimum carry dirt Dye, this is conducive to cleaning.Also by reducing sample contact, such as using contactless mixing and the distribution of contactless reagent, make waste Stream minimizes.Because these assemblies are from not in contact with sample, they can infinitely be reused it is not necessary to cleaning or changing.Pass through Make experiment reagent volume minimization used, analyzer can also make cost minimization.

For so that reagent consumption is minimized, increasing patient throughput, low sample volume is important, and in patient's bag In the case of including the people of baby, the elderly or the low sample of other generation, promote inspection.Also make to need minimum to preparation of samples The collection changing or eliminating the small sample volume of this needs needs the potential unordered and mixed of quick screening to a large amount of patients wherein It is beneficial in random environment.

Analyzer managing patient information in a secured manner, and provide in hospital database system, central command and diagnosis Person and reagent in bulk resupply between communication.Safeguard and demand for services is minimized to routine work, wherein device is in short installation Just can operate in time, and can continuously run several days.

Description.Sample (Figure 37) is delivered by sample tracking system.Analyzer (Figure 38) has 2 circular rotating disks and passes Send band (Figure 40).One carousel is for sample, and one is for reagent bag.It is presented herein below for mixing in carousel The sub-portfolio device that conjunction, temperature control, imaging and magnetic select.This analyzer also provides the space of analyzer sub-component, institute State the storage (such as water and cleaner) of sub-component such as pump, electronic device and power supply and waste and bulk liquids reagent.Crucial Function element is as shown in Figure 40 and Figure 39.Sample disc conveyer belt has reusable cup, mixes cup（Wherein sample connects Tactile reagent）And reaction cup（The mixture (reactant mixture) of wherein sample and reagent covers on dyestuff mat）2 with one heart Circle.Reaction cup, through magnet, is selected.After magnetic selects, through imaging system, it is obtained reaction cup using photodetector array Take low magnification image.This imaging system is high-resolution focusing system, and it has LED as light source, and has transmitting and swash Send out filter, to allow fluorescence signal emitting portion（For example,Fluorescent particle (Invitrogen, catalog number (Cat.No.) F-8813)）One-tenth Picture.After Image Acquisition, there is the computer disposal image of the loading of customization software, and need to deliver result according to user.

Reaction cup and mixing cup are all reusable；The cleaning of reaction cup occurs after imaging.The cleaning of mixing cup Any time point after reactant mixture is to reaction cup transfer can occur.Cup cleaning systems (Figure 40) are single using having The pipette robot of shifting axle is reducing Residual contamination.Dry station guarantees, before adding sample, existing in each cup can be again The liquid now measured.

Complete schematic diagram conceptually similar to the line map shown in the analyzer in embodiment 14 because having fixed cup The rotary carousel of son allows format high throughput, and continuous processing is reacted.Most important difference has been to provide second rotational circle Disk conveyer belt, it can accommodate the reagent of 100 different experiments, and such as this analyzer is loaded with complete needed for the multiple test of execution Portion's reagent.

With bar code labelled reagent bag.The scanning of bar code can provide information, the such as position of reagent bag for analyzer software Put, the identity of reagent and need the correction file etc. using.Load software notifies user to change reagent as needed in time Bag.Reagent bag carousel provides the temperature control of reagent.

Conclusion.This analyzer shows that adaptation is used magnetic force as the test shape of the selection power specifically capturing target The exploitation of the system of formula.The nothing that it is integrated with for target zooms into the photodetector array detector of picture and Load Images divide Analysis.It provides ultra high throughput and waste containment.

Alternate embodiment.There are many potential changes, those listed in describing in detail including superincumbent device.Permissible Adjustment circulation time, to adapt to the parameter needed for special test.Described device can use disposable cup or suction nozzle, this Can aid in and make Residual contamination and minimizing cross-contamination.Described device can include more or less of reagent pipette, Each of which can be close to one or more reagent.The replacement that display in Figure 59 can be used is dried suction nozzle design, or permissible Using using capillary replacement sample collection running stores (Figure 60).Sample input can substitute sample with combination unit and move Liquid device, described combination unit deposits the sample directly from shuttle, such as shown in Figure 61.

Sample inputs.After user puts into sample in sample tracking system, analyzer scans sample bar code, and checks Needed which test.If necessary it is allowed to manually enter the data of stat sample.If sample requires more than 1 test, sample The aliquot of same sample can be delivered to multiple holes by subsystem.

Mixing and incubation.In mixing cup, sample contacts reagent.Reagent in addition to sample is added by pipette robot Enter.According to test, one or more reagent can be added, and add order can change.This analyzer has mixed （To realize the mixing of sample and reagent）And temperature control（To maintain the reaction of fixed temperature）.

Cleaning.Cleaning can be realized by blood plasma cleaner, and it can be used for cleaning suction nozzle and cup.In order to ensure minimum is taken Band pollution, cleaning can include the step pre-processing or being coated surface；This be coated or pre-treatment step can be used for increase or Reduce the wettability on surface.

Claims (20)

1. a kind of imaging analysis instrument, it comprises：

A) housing, described housing accepts to comprise the shuttle that sample inputs holder and detection zone, and described detection zone has >= The line of shortest length size of 1mm, for detecting target, wherein said shuttle contains sample；

B) cause the mechanism that liquid flows in described shuttle, sample is moved to institute from described sample input holder State detection zone, wherein said container is sealed with reaction basic structure by the fluid management being designed to need outside to start fluid transfer Close；

C) it is used for selection power putting on the assembly of described shuttle, so that the particle being arranged in described sample is deposited on On described detection zone；

D) photoelectric array detector configuring for the large area imaging of detection zone；

E) image forming optics less than 5 times are amplified, described image forming optics are arranged to the optical signal in Autonomous test in future area Project on photoelectric array detector；With

F) computer, described computer is programmed for using the figure comprising pixel threshold analysis and pixel connectivity algorithm As analysis software detection is deposited on the individual particle on described detection surface.

2. analyzer as claimed in claim 1, wherein said selection power can be to be more than in the liquid of described shuttle The average speed rolling average diameter of 0.5mm/min is less than 0.5mm and averag density is less than 2g/cm³Magnetic-particle be more than 5mm Distance, described shuttle is maintained at the fixed position of described analyzer, the density of wherein said liquid and viscosity and salt solution It is substantially identical.

3. analyzer as claimed in claim 1, the wherein said device for applying selection power includes having more than 10mm's The shortest linear size and the magnet of the intensity of magnetization more than 3.5 kJ (kilojoule)s/cubic meter.

4. analyzer as claimed in claim 1, wherein said image forming optics amplify less than 2 times or without any amplification.

5. analyzer as claimed in claim 1, wherein said analyzer comprises automatically to assemble.

6. analyzer as claimed in claim 1, wherein said analyzer comprises for guaranteeing described detector and in described inspection Survey the mechanism of the fixed range between the described sample holder surface near device.

7. analyzer as claimed in claim 1, shuttle described in wherein said analyzer irradiation.

8. analyzer as claimed in claim 1, wherein said analyzer comprises luminous two for shuttle described in irradiation Pole pipe.

9. analyzer as claimed in claim 1, wherein said analyzer is received and is imported as single or as multiple units Described shuttle.

10. analyzer as claimed in claim 1, wherein said analyzer comprises can be between the position on described analyzer The robot stand of mobile example container.

11. analyzers as claimed in claim 1, wherein said analyzer comprises can be between the position on described analyzer The carousel mechanism of mobile example container.

12. analyzers as claimed in claim 1, wherein said analyzer comprises can be between the position on described analyzer The mechanical tracking mechanism of mobile example container.

13. analyzers as claimed in claim 1, wherein said analyzer comprises bar code readings bar code device.

14. analyzers as claimed in claim 1, wherein said analyzer comprises incubator, and its described shuttle is received In shell, described shell is stably maintained at the mean temperature in 2 degrees Celsius of temperature set-point.

15. analyzers as claimed in claim 1, wherein said analyzer comprises printer, electronic monitor and/or is used for even Connect the system of external communication network.

16. analyzers as claimed in claim 1, wherein said analyzer comprises the device for automated cleaning shuttle, Described shuttle is reused in described analyzer.

17. analyzers as claimed in claim 1, wherein said analyzer comprises one or more one-tenth on described analyzer As being followed by the recipient by shuttle.

18. analyzers as claimed in claim 1, wherein said analyzer comprises one or more waste liquid recipients.

19. analyzers as claimed in claim 1, wherein said analyzer comprises integrated planning software, for management one Or movement between the diverse location of described analyzer for more shuttles.

20. analyzers as claimed in claim 1, the shuttle having more than 8mm height received by wherein said analyzer.